Pentacyclic compounds, intermediates, processes, compositions, and methods

ABSTRACT

The present invention provides compounds of formula I and II: ##STR1## wherein X is --O--, --S--, or --NR 5  --; 
     Y is --O--, --S--, --CH 2  --, --CH 2  CH 2  --, --CH═CH--, or --NR 5  --; 
     B is --CH 2  -- or --CO--; 
     R 1 , R 2 , and R 3  are each independently --H, --OH, --O(C 1  -C 4  alkyl), --OCOC 6  H 5 , --OCO(C 1  -C 6  alkyl), --OSO 2  (C 4  -C 6  alkyl), --OSO 2  CF 3 , Cl, or F; 
     n is 1 or 2; 
     W is CH 2  or C═O; 
     R 4  is 1-piperidinyl, 2-oxo-1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino; 
     R 5  is C 1  -C 3  alkyl, --COC 6  H 5 , --CO(C 1  -C 6  alkyl), --C(O)OC 6  H 5 , --C(O)O(C 1  -C 6  alkyl), --SO 2  (C 1  -C 6  alkyl), --SO 2  C 6  H 5 , or --SO 2  CF 3  ; 
     or a pharmaceutically acceptable salt or solvate thereof.

This application is a continuation of application Ser. No. 08/878,799,filed Jun. 19, 1997 which is a division of Ser. No. 08/696,279, filedAug. 13, 1996, U.S. Pat. No. 5,726,186, which claims priority toprovisional application Ser. No. 60/003,496, filed Sep. 8, 1995.

FIELD OF THE INVENTION

This invention relates to the fields of pharmaceutical and organicchemistry and provides novel pentacyclic compounds which are useful forthe treatment of the various medical indications associated withpost-menopausal syndrome, and uterine fibroid disease, endometriosis,and aortal smooth muscle cell proliferation. The present inventionfurther relates to intermediate compounds and processes useful forpreparing the pharmaceutically active compounds of the presentinvention, and pharmaceutical compositions.

BACKGROUND OF THE INVENTION

"Post-menopausal syndrome" is a term used to describe variouspathological conditions which frequently affect women who have enteredinto or completed the physiological metamorphosis known as menopause.Although numerous pathologies are contemplated by the use of this term,three major effects of post-menopausal syndrome are the source of thegreatest long-term medical concern: osteoporosis, cardiovascular effectssuch as hyperlipidemia, and estrogen-dependent cancer, particularlybreast and uterine cancer.

Osteoporosis describes a group of diseases which arise from diverseetiologies, but which are characterized by the net loss of bone mass perunit volume. The consequence of this loss of bone mass and resultingbone fracture is the failure of the skeleton to provide adequatestructural support for the body. One of the most common types ofosteoporosis is that associated with menopause. Most women lose fromabout 20% to about 60% of the bone mass in the trabecular compartment ofthe bone within 3 to 6 years after the cessation of menses. This rapidloss is generally associated with an increase of bone resorption andformation. However, the resorptive cycle is more dominant and the resultis a net loss of bone mass. Osteoporosis is a common and serious diseaseamong post-menopausal women.

There are an estimated 25 million women in the United States, alone, whoare afflicted with this disease. The results of osteoporosis arepersonally harmful and also account for a large economic loss due itschronicity and the need for extensive and long term support(hospitalization and nursing home care) from the disease sequelae. Thisis especially true in more elderly patients. Additionally, althoughosteoporosis is not generally thought of as a life threateningcondition, a 20% to 30% mortality rate is related with hip fractures inelderly women. A large percentage of this mortality rate can be directlyassociated with post-menopausal osteoporosis.

The most vulnerable tissue in the bone to the effects of post-menopausalosteoporosis is the trabecular bone. This tissue is often referred to asspongy or cancellous bone and is particularly concentrated near the endsof the bone (near the joints) and in the vertebrae of the spine. Thetrabecular tissue is characterized by small osteoid structures whichinter-connect with each other, as well as the more solid and densecortical tissue which makes up the outer surface and central shaft ofthe bone. This inter-connected network of trabeculae gives lateralsupport to the outer cortical structure and is critical to thebio-mechanical strength of the overall structure. In post-menopausalosteoporosis, it is, primarily, the net resorption and loss of thetrabeculae which leads to the failure and fracture of bone. In light ofthe loss of the trabeculae in post-menopausal women, it is notsurprising that the most common fractures are those associated withbones which are highly dependent on trabecular support, e.g., thevertebrae, the neck of the weight bearing bones such as the femur andthe fore-arm. Indeed, hip fracture, collies fractures, and vertebralcrush fractures are hall-marks of post-menopausal osteoporosis.

At this time, the only generally accepted method for treatment ofpost-menopausal osteoporosis is estrogen replacement therapy. Althoughtherapy is generally successful, patient compliance with the therapy islow primarily because estrogen treatment frequently produces undesirableside effects.

Throughout premenopausal time, most women have less incidence ofcardiovascular disease than age-matched men. Following menopause,however, the rate of cardiovascular disease in women slowly increases tomatch the rate seen in men. This loss of protection has been linked tothe loss of estrogen and, in particular, to the loss of estrogen'sability to regulate the levels of serum lipids. The nature of estrogen'sability to regulate serum lipids is not well understood, but evidence todate indicates that estrogen can upregulate the low density lipid (LDL)receptors in the liver to remove excess cholesterol. Additionally,estrogen appears to have some effect on the biosynthesis of cholesterol,and other beneficial effects on cardiovascular health.

It has been reported in the literature that post-menopausal women havingestrogen replacement therapy have a return of serum lipid levels toconcentrations to those of the pre-menopausal state. Thus, estrogenwould appear to be a reasonable treatment for this condition. However,the side-effects of estrogen replacement therapy are not acceptable tomany women, thus limiting the use of this therapy. An ideal therapy forthis condition would be an agent which would regulate the serum lipidlevel as does estrogen, but would be devoid of the side-effects andrisks associated with estrogen therapy.

The third major pathology associated with post-menopausal syndrome isestrogen-dependent breast cancer and, to a lesser extent,estrogen-dependent cancers of other organs, particularly the uterus.Although such neoplasms are not solely limited to a post-menopausalwomen, they are more prevalent in the older, post-menopausal population.Current chemotherapy of these cancers has relied heavily on the use ofanti-estrogen compounds such as, for example, tamoxifen. Although suchmixed agonist-antagonists have beneficial effects in the treatment ofthese cancers, and the estrogenic side-effects are tolerable in acutelife-threatening situations, they are not ideal. For example, theseagents may have stimulatory effects on certain cancer cell populationsin the uterus due to their estrogenic (agonist) properties and they may,therefore, be contraproductive in some cases. A better therapy for thetreatment of these cancers would be an agent which is an anti-estrogencompound having negligible or no estrogen agonist properties onreproductive tissues.

In response to the clear need for new pharmaceutical agents which arecapable of alleviating the symptoms of, inter alia, post-menopausalsyndrome, the present invention provides new pentacyclic compounds,pharmaceutical compositions thereof, and methods of using such compoundsfor the treatment of post-menopausal syndrome and other estrogen-relatedpathological conditions such as those mentioned below.

Uterine fibrosis (uterine fibroid disease) is an old and ever presentclinical problem which goes under a variety of names, including uterinefibroid disease, uterine hypertrophy, uterine lieomyomata, myometrialhypertrophy, fibrosis uteri, and fibrotic metritis. Essentially, uterinefibrosis is a condition where there is an inappropriate deposition offibroid tissue on the wall of the uterus.

This condition is a cause of dysmenorrhea and infertility in women. Theexact cause of this condition is poorly understood but evidence suggeststhat it is an inappropriate response of fibroid tissue to estrogen. Sucha condition has been produced in rabbits by daily administrations ofestrogen for 3 months. In guinea pigs, the condition has been producedby daily administration of estrogen for four months. Further, in rats,estrogen causes similar hypertrophy.

The most common treatment of uterine fibrosis involves surgicalprocedures both costly and sometimes a source of complications such asthe formation of abdominal adhesions and infections. In some patients,initial surgery is only a temporary treatment and the fibroids regrow.In those cases a hysterectomy is performed which effectively ends thefibroids but also the reproductive life of the patient. Also,gonadotropin releasing hormone antagonists may be administered, yettheir use is tempered by the fact they can lead to osteoporosis. Thus,there exists a need for new methods for treating uterine fibrosis, andthe methods of the present invention satisfy that need.

Endometriosis is a condition of severe dysmenorrhea, which isaccompanied by severe pain, bleeding into the endometrial masses orperitoneal cavity and often leads to infertility. The cause of thesymptoms of this condition appear to be ectopic endometrial growthswhich respond inappropriately to normal hormonal control and are locatedin inappropriate tissues. Because of the inappropriate locations forendometrial growth, the tissue seems to initiate local inflammatory-likeresponses causing macrophage infiltration and a cascade of eventsleading to initiation of the painful response. The exact etiology ofthis disease is not well understood and its treatment by hormonaltherapy is diverse, poorly defined, and marked by numerous unwanted andperhaps dangerous side effects.

One of the treatments for this disease is the use of low dose estrogento suppress endometrial growth through a negative feedback effect oncentral gonadotropin release and subsequent ovarian production ofestrogen; however, it is sometimes necessary to use continuous estrogento control the symptoms. This use of estrogen can often lead toundesirable side effects and even the risk of endometrial cancer.

Another treatment consists of continuous administration of progestinswhich induces amenorrhea and by suppressing ovarian estrogen productioncan cause regressions of the endometrial growths. The use of chronicprogestin therapy is often accompanied by the unpleasant CNS sideeffects of progestins and often leads to infertility due to suppressionof ovarian function.

A third treatment consists of the administration of weak androgens,which are effective in controlling the endometriosis; however, theyinduce severe masculinizing effects. Several of these treatments forendometriosis have also been implicated in causing a mild degree of boneloss with continued therapy. Therefore, new methods of treatingendometriosis are desirable.

Smooth aortal muscle cell proliferation plays an important role indiseases such as atherosclerosis and restenosis. Vascular restenosisafter percutaneous transluminal coronary angioplasty (PTCA) has beenshown to be a tissue response characterized by an early and late phase.The early phase occurring hours to days after PTCA is due to thrombosiswith some vasospasms while the late phase appears to be dominated byexcessive proliferation and migration of aortal smooth muscle cells. Inthis disease, the increased cell motility and colonization by suchmuscle cells and macrophages contribute significantly to thepathogenesis of the disease. The excessive proliferation and migrationof vascular aortal smooth muscle cells may be the primary mechanism tothe reocclusion of coronary arteries following PTCA, atherectomy, laserangioplasty and arterial bypass graft surgery. See "IntimalProliferation of Smooth Muscle Cells as an Explanation for RecurrentCoronary Artery Stenosis after Percutaneous Transluminal CoronaryAngioplasty," Austin et al., Journal of the American College ofCardiology, 8: 369-375 (August 1985).

Vascular restenosis remains a major long term complication followingsurgical intervention of blocked arteries by percutaneous transluminalcoronary angioplasty (PTCA), atherectomy, laser angioplasty and arterialbypass graft surgery. In about 35% of the patients who undergo PTCA,reocclusion occurs within three to six months after the procedure. Thecurrent strategies for treating vascular restenosis include mechanicalintervention by devices such as stents or pharmacologic therapiesincluding heparin, low molecular weight heparin, coumarin, aspirin, fishoil, calcium antagonist, steroids, and prostacyclin. These strategieshave failed to curb the reocclusion rate and have been ineffective forthe treatment and prevention of vascular restenosis. See "Prevention ofRestenosis after Percutaneous Transluminal Coronary Angioplasty: TheSearch for a `Magic Bullet`," Hermans et al., American Heart Journal,122: 171-187 (July 1991).

In the pathogenesis of restenosis excessive cell proliferation andmigration occurs as a result of growth factors produced by cellularconstituents in the blood and the damaged arterial vessel wall whichmediate the proliferation of smooth muscle cells in vascular restenosis.

Agents that inhibit the proliferation and/or migration of smooth aortalmuscle cells are useful in the treatment and prevention of restenosis.The present invention provides for the use of compounds as smooth aortalmuscle cell proliferation inhibitors and, thus inhibitors of restenosis.

Transforming growth factor-β (TGF-β) is a peptide growth factor whichrefers to a generic family of peptides, often called isoforms meaningthat members of the family either share amino acid homology and/or havesimilar physiological actions. The TCF-β's, particularly thosedesignated TGF-β₁, β₂, and β₃, are particularly associated withprocesses involved in tissue repair and diseases associated withabnormal repair processes (see, Sporn and Roberts "The TransformingGrowth Factor-β's", Peptide Growth Factors and their Receptors I,419-472 (Berlin: Springer Verlag, 1990)).

Agents which induce the production of TGF-β's, and in particular TGF-β₃,are useful in promoting tissue repair and treating diseases whichinvolve abnormal tissue repair. Such utilities include but are notlimited to wound-healing, reduction of scarring (see, Ferguson, "WoundHealing, Scarring, TGF-β Antagonists, and Isoforms", Abst. NIH TGF-βSymposium, Bethesda MD, May 3, 1994), and ulcerative mucositis inducedby chemotherapy and radiotherapy (see, Sonis and Haley, "Prevention ofChemotherapy-Induced Ulcerative Mucositis by Transforming GrowthFactor-β₃ ", Abst. NIH TGF-β Symposium, Bethesda MD, May 3, 1994). Thepresent invention provides for the use of compounds as promoters oftissue repair processes and as treatments for diseases involvingabnormal tissue repair.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I ##STR2## whereinX is --O--, --S--, or --NR⁵ --;

Y is --O--, --S--, --CH₂ --, --CH₂ CH₂ --, --CH═CH--, or --NR⁵ --;

R¹, R², and R³ are each independently --H, --OH, --O(C₁ -C₄ alkyl),--OCOC₆ H₅, --OCO(C₁ -C₆ alkyl), --OSO₂ (C₄ -C₆ alkyl), --OSO₂ CF₃, Cl,or F;

n is 1 or 2;

W is CH₂ or C═O;

R⁴ is 1-piperidinyl, 2--Oxo-1-piperidinyl, 1-pyrrolidinyl,methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 2--Oxo-1-pyrrolidinyl,4-morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino;

R⁵ is C₁ -C₃ alkyl, --COC₆ H₅, --CO(C₁ -C₆ alkyl), --C(O)OC₆ H₅,--C(O)O(C₁ -C₆ alkyl), --SO₂ (C₁ -C₆ alkyl), --SO₂ C₆ H₅, or --SO₂ CF₃ ;

or a pharmaceutically acceptable salt thereof.

Also provided by the present invention are compounds of formula II##STR3## wherein B is --CH₂ -- or --CO--

Y, R¹, R², R³, R⁴, n, and W are as defined above; or a pharmaceuticallyacceptable salt thereof.

Also provided by the present invention are intermediate compounds offormula III and VI which are useful for preparing the pharmaceuticallyactive compounds of the present invention, and are shown below ##STR4##wherein R^(1a), R^(2a), and R^(3a) are each independently --H, --O(C₁-C₄ alkyl), --Cl, --F, or a suitably protected hydroxyl;

Z is --OH, --OC₆ H₅, --O(C₁ -C₄ alkyl), or 4-hydroxyphenyl;

X and Y are as defined above; ##STR5## wherein R^(1a), R^(2a), R^(3a),and Y are as defined above.

The present invention further relates to pharmaceutical compositionscontaining compounds of formula I or formula II, optionally containingestrogen or progestin, and the use of such compounds, alone, or incombination with estrogen or progestin, for alleviating the symptoms ofpost-menopausal syndrome, particularly osteoporosis, cardiovascularrelated pathological conditions, and estrogen-dependent cancer. As usedherein, the term "estrogen" includes steroidal compounds havingestrogenic activity such as, for example, 17b-estradiol, estrone,conjugated estrogen (Premarin®), equine estrogen, 17a-ethynyl estradiol,and the like. As used herein, the term "progestin" includes compoundshaving progestational activity such as, for example, progesterone,norethylnodrel, nongestrel, megestrol acetate, norethindrone, and thelike.

The compounds of the present invention also are useful for inhibitinguterine fibroid disease and endometriosis in women and aortal smoothmuscle cell proliferation, particularly restenosis, in humans.

Also provided by the present invention is a process for preparing acompound of formula Ia ##STR6## wherein R^(1a), R^(2a), and R^(3a) areeach independently --H, --O(C₁ -C₄ alkyl), --Cl, --F, or a suitablyprotected hydroxyl;

X and Y are as defined above;

G is --OH or --O(CH₂)_(n) WR⁴

wherein

n, W, and R⁴ are as defined above;

or a pharmaceutically acceptable salt thereof, which comprises

a) reacting a compound of formula IIIa ##STR7## wherein R^(1a), R^(2a),R^(3a), X, and Y are as defined above;

Z^(a) is --OH, --OC₆ H₅, --O(C₁ -C₄ alkyl), with a Grignard reagent offormula IVa ##STR8## wherein G^(a) is --OSi(CH₃) 3, a suitably protectedhydroxyl which can be selectively deprotected in the presence of R^(1a),R^(2a), and R^(3a), or --O(CH₂)_(n) WR⁴

wherein

n, W, and R⁴ are as defined above;

b) when G^(a) is --OSi(CH₃)₃ or another suitable protecting groupoptionally removing the said protecting group and thereafter reactingthe resulting --OH with Q--(CH₂)_(n) --W--R⁴ wherein Q is bromo, chloro,or hydroxy; and

c) optionally salifying the reaction product from step a) or b).

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention includes compounds of formula I##STR9## wherein X is --O--, --S--, or --NR⁵ --;

Y is --O--, --S--, --CH₂ --, --CH₂ CH₂ --, --CH═CH--, or --NR⁵ --;

R¹, R², and R³ are each independently --H, --OH, --O(C₁ -C₄ alkyl),--OCOC₆ H₅, --OCO(C₁ -C₆ alkyl), --OSO₂ (C₄ -C₆ alkyl), --OSO₂ CF₃, Cl,or F;

n is 1 or 2;

W is CH₂ or C═O;

R⁴ is 1-piperidinyl, 2--Oxo-1-piperidinyl, 1-pyrrolidinyl,methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 2--Oxo-1-pyrrolidinyl,4-morpholino, dimethylamino, diethylamino, or 1-hexamethyleneimino;

R⁵ is C₁ -C₃ alkyl, --COC₆ H₅, --CO(C₁ -C₆ alkyl), --C(O)OC₆ H₅,--C(O)O(C₁ -C₆ alkyl), --SO₂ (C₁ -C₆ alkyl), --SO₂ C₆ H₅, or --SO₂ CF₃ ;

or a pharmaceutically acceptable salt thereof.

General terms used in the description of compounds herein described beartheir usual meanings. For example, "C₁ -C₆ alkyl" refers to straight orbranched aliphatic chains of 1 to 6 carbon atoms including methyl,ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl, hexyl,isohexyl, and the like.

The starting material for one route of preparing compounds of thepresent invention are compounds of formula V below, ##STR10## whereinR^(1a), R^(2a), and R^(3a) are each independently --H, --O(C₁ -C₄alkyl), --F, --Cl, or a suitably protected hydroxyl;

X and Y are as defined above;

One embodiment of this starting material, compounds of formula Vb##STR11## wherein R^(1a), R^(2a), and R^(3a) are as defined above;

X' is --O--, --S--, or --NH--;

are made essentially as described in Journal of Organic Chemistry,40:3169 (1975). Preferably, R^(1a) and R^(2a) are methoxy or a suitablyprotected hydroxyl, R^(3a) is --H, and X' is --O--.

In general, a readily available thioindoxyl of the formula ##STR12##wherein R^(2a) is as defined above, is reacted with a benzaldehyde ofthe formula ##STR13## wherein X^(b) is --OH, --SH, or --NH₂ and R^(1a)and R^(2a) are as defined above. The reaction generally is carried outin the presence of a mild base such as triethylamine and a proticsolvent such as ethanol, and is run at ambient temperature or below. Theproduct of this condensation is then dehyrogenated by various methodsknown in the art, most preferably via reaction with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to give a compound offormula V.

If so desired, a compound of formula V in which R^(1b), R^(2b), and/orR^(3b) is methoxy may be deprotected by reaction with aluminumtrichloride and ethanethiol and reprotected with an alternative phenolprotecting group at this stage. Protecting groups which are removableunder mild conditions such as t-butyldimethylsilyl are preferred.

Alternative starting materials of formula Vc ##STR14## wherein R^(1c)and R^(2c) are suitably protected hydroxyls; are available by standardprotection of commercially available coumestrol. Protecting groups whichare removable under mild conditions such as t-butyldimethylsilyl arepreferred.

Starting materials of formula Vd ##STR15## wherein R^(1a), R^(2a), andR^(3a) are as defined above;

X" is --O-- or --S--; and

Y" is --CH₂ --, --CH₂ --CH₂ --, or --CH═CH--, are prepared by vonPechman reaction as described in Organic Reactions, 7:1 (1953).

In general, a readily available tetralone or indanone of the formula##STR16## wherein R^(2a) is as defined above, and y^(d) is --CH₂ -- or--CH₂ --CH₂ --, is condensed with an appropriately substituted phenol orthiophenol: ##STR17## wherein R^(1a) ' is --OH, --H, --O(C₁ -C₄ alkyl),--F, --Cl, or a suitably protected hydroxyl;

R^(3a) is as defined above; and

X^(d) is --OH or --SH,

under the influence of a condensing agent such as phosphorusoxychloride, phosphorus pentoxide, sulfuric acid, aluminum chloride orthe like. Preferably R^(1a) ' is --OH, R^(3a) is --H, X^(d) is OH, Y^(d)is CH₂ CH₂, and R^(2a) is methoxy and the reaction is carried out intoluene or benzene at 80-110° C. utilizing phosphorus oxychloride as thecondensing agent.

If the von Pechman product contains a phenolic moiety it may beprotected at this stage, or alternatively if R^(2f) is methoxy, it maybe subjected to a delalkylation/reprotection sequence as describedsupra. If so desired, the optional double bond may then be installed byreaction with DDQ or another dehydrogenating agent.

Additional starting materials of formula Ve ##STR18## wherein X^(e) andY^(e) are each independently --O--, --S--, --NH--, or --NR⁵ ;

R^(1a), R^(2a), R^(3a), and R⁵ are as defined above; are preparedessentially as described in Heterocycles, 35:1425 (1993); U.S. Pat. No.5,073,553 issued Dec. 17, 1991; and Indian Journal of Chemistry, 24B:556 (1989).

Other starting materials, of the formula ##STR19## wherein R^(1a),R^(2a), and R^(3a) are as defined above;

X^(f) is --NH-- or --NR⁵ --; and

Y^(f) is --CH₂ --, --CH₂ --CH₂ --, or --CH═CH, are prepared essentiallyas described in Indian Journal of Chemistry, 14B: 132 (1976) and inJournal of the Chemical Society, Perkin Trans. I, 1747 (1974). If thedouble bond (Y^(f) ═--CH═CH--) is desired, it may be obtained in themanner described supra, by the use of DDQ.

Once a compound of formula V, has been formed, one option allows forreduction of the selected formula V compound to a compound of formulaIIIb ##STR20## wherein

R^(1a), R^(2a), R^(3a), X, and Y are as defined above; by reaction withan appropriate reducing agent such as diisobutylaluminum hydride in asolvent such as toluene, CH₂ Cl₂, or THF. Generally this reduction iscarried out at a temperature below 0° C. and preferably between -50° C.and -100° C. The formula IIIb compound may then be converted, either insitu or in a separate step to a compound of formula IIIc below ##STR21##wherein R⁶ is --C₁ -C₄ alkyl or --C₆ H₅ or

R^(1a), R^(2a), R^(3a), X, and Y are as defined above;

by reaction with an alcohol or phenol R⁶ OH and, optionally an acidiccompound or dehydrating agent such as magnesium sulfate. It ispreferable to carry out this conversion in a separate step, in CH₂ Cl₂or chlorobenzene, between ambient temperature and reflux. Preferably,R^(1a) and R^(2a) are suitably protected hydroxyls, R^(3a) is H, X is--O--, Y is --O-- or --S--, and R⁶ is --C₆ H₅.

Alternatively, a compound of formula V in which X is --NH-- may beacylated on nitrogen and then directly converted to a formula IIIccompound by reaction with NaBH₄ or a similar reducing agent in thepresence of an acidic compound such as HCl and an alcoholic solvent. Inthis embodiment of IIIc it is preferable that R^(1a) and R^(2a) aremethoxy, R^(3a) is H, X is --N(COC₆ H₅)-- or --N(COC(CH₃)₄)--, Y is--O--, and R⁶ is preferably --C₂ H₅.

In the next step, a formula IIIb or IIIc compound is reacted with anaryl Grignard reagent of formula ##STR22## wherein G^(a) is --OSi(CH₃)₃,a suitably protected hydroxyl which can be selectively deprotected inthe presence of R^(1a) and R^(2a), or --(CH₂)_(n) WR⁴ ;

wherein

n, W, and R⁴ are as defined above; in a solvent such as toluene, THF,diethyl ether, CH₂ Cl₂, or a mixture thereof and at ambient temperatureor below. Optionally, the reaction may be facilitated by the presence ofa Lewis acid such as boron trifluoride etherate, tin tetrachloride,titanium tetrachloride or the like.

When G^(a) of formula IVa is --O(CH₂)_(n) WR⁴ this Grignard reactionprovides a compound of formula Ib ##STR23## wherein R^(1a), R^(2a), andR^(3a) are each independently --H, --O(C₁ -C₄ alkyl), --Cl, --F, or asuitably protected hydroxyl;

X, Y, n, W, and R⁴ are as defined above; which can be optionallydeprotected and derivatized as described infra to provide the desiredformula I compound.

Alternatively, when G^(a) of formula IVa is --OSi(CH₃)₃ or anothersuitably protected hydroxyl, the protecting group is cleaved at thisstage under conditions which leave R^(1a), R^(2a), and R^(3a) intact, toprovide a compound of formula Ic ##STR24## wherein R^(1a), R^(2a),R^(3a), X, and Y are as defined above. Such conditions are dependentupon the nature of the protecting groups and are known to those skilledin the art [see, e.g., Greene and Wuts, Protective Groups in OrganicSynthesis, 2nd ed., (1991)]. In a preferred embodiment, in which R^(1a)and R^(2a) are t-butyldimethylsilyloxy or methoxy, R^(3a) is H, andG^(a) is --OSi(CH₃)₄ this may be accomplished by brief exposure to amethanolic slurry of potassium carbonate at ambient temperature or belowin the presence of a cosolvent such as THF or diethyl ether.

A formula Ic compound may be converted to a formula Ib compound byutilizing one of the synthetic routes shown in Scheme I. In Scheme I,R^(1a), R^(2a), R^(3a), R⁴, W, X, Y, and n are as defined above.##STR25## Each step of Scheme I is carried out via procedures well knownto one of ordinary skill in the art.

For example, a formula Ic compound can be reacted with a compound of theformula

    R.sup.4 --W--(CH.sub.2).sub.n --Q

wherein R⁴, W, and n are as defined above and Q is a bromo or,preferably, a chloro moiety, to provide compounds of formula Ib. Thisalkylation is normally achieved by carrying out the reaction in thepresence of an excess of finely powdered potassium carbonate and usingan equivalent to slight excess of the Q--(CH₂)--R³ reactant.

A more preferred method involves the reaction of a formula Ic compoundwith a compound of formula

    R.sup.4 --W--(CH.sub.2).sub.n --OH

wherein R⁴, W, and n are as defined above in the presence oftriphenylphosphine, diethyl azodicarboxylate (DEAD), and an appropriatesolvent, resulting in a formula Ib compound. This process is known inthe art as a Mitsunobu coupling. Preferably, 2-4 equivalents of1-(2-hydroxyethyl)pyrrolidine are reacted with a formula Ic compound inthe presence of 2-5 equivalents each of triphenylphosphine and DEAD, inan inert solvent such as toluene at ambient temperature. At thistemperature the reaction only takes about 30 minutes to about 3 hours,however changes in the reaction conditions will influence the amount oftime this reaction needs to be run to completion. Of course, theprogress of this reaction step can be monitored via standardchromatographic techniques.

In yet another synthetic route, a formula Ic compound is reacted with anexcess of an alkylating agent of the formula

    J--W--(CH.sub.2).sub.n --J'

wherein J and J' each are the same or different leaving group, in analkali solution.

Appropriate leaving groups include, for example, the sulfonates such asmethanesulfonate, 4-bromosulfonate, toluenesulfonate, ethanesulfonate,isopropanesulfonate, 4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate,2-chlorobenzene sulfonate, and the like, halogens such as bromo, chloro,iodo, and the like, and other related groups.

A preferred alkylating agent is 1,2-dibromoethane, and at least 2equivalents, preferably, more than 2 equivalents, of 1,2-dibromoethaneis used per equivalent of substrate.

A preferred alkali solution for this alkylation reaction containspotassium carbonate in an inert solvent such as, for example, methyethylketone (MEK) or DMF. In this solution, the 4-hydroxy group of thebenzoyl moiety of a formula IIId compound exists as a phenoxide ionwhich displaces one of the leaving groups of the alkylating agent.

This reaction is best run when the alkali solution containing thereactants and reagents is brought to reflux and allowed to run tocompletion. When using MEK as the preferred solvent, reaction times runfrom about 6 hours to about 20 hours.

Alternatively, a compound of formula Id can be prepared by the reactionof an alcohol of formula

    J--W--(CH.sub.2).sub.n --OH

wherein J is selected from the leaving groups described above, with aformula Ic compound via a Mitsunobu coupling procedure. A preferredalcohol is 2-bromoethanol.

The reaction product from this step, a compound of formula Id, is thenreacted with 1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine,dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine, or1-hexamethyleneimine, via standard techniques, to form compounds offormula Ib. Preferably, the hydrochloride salt of piperidine is reactedwith the formula Ib compound in an inert solvent, such as anhydrous DMF,and heated to a temperature in the range from about 60° C. to about 110°C. When the mixture is heated to a preferred temperature of about 90°C., the reaction only takes about 30 minutes to about 1 hour. However,changes in the reaction conditions will influence the amount of timethis reaction needs to be run to completion. Of course, the progress ofthis reaction step can be monitored via standard chromatographictechniques.

Dealkylation/deprotection of terminally-protected hydroxy groups informula Ia compounds can be carried out if so desired to providepharmaceutically active compounds of formula I, via procedures known toone of ordinary skill in the art. A preferred method for thedeprotection of t-butyldimethylsilylethers, a preferred embodiment ofR^(1a) and R^(2a), involves stirring them in an appropriate solvent suchas THF with a soluble fluoride source such as tetra-n-butylammoniumfluoride at ambient temperature.

The above procedures provide novel, pharmaceutically active compounds offormula I in which R¹, R², and R³ each are hydrogen, hydroxy, C₁ -C₄alkoxy, chloro, or fluoro. Preferred formula Ia compounds are those inwhich R¹ and R² each are methoxy, or R¹ and R² each are hydroxy, R³ isH, R⁴ is piperidinyl or pyrrolidinyl, X is --O--, Y is --S--, W is --CH₂--, and n is 1. These preferred compounds, as well as other formula Iacompounds, can be used as pharmaceutical agents or can be furtherderivitized to provide other formula I compounds which also are usefulfor practicing the methods of the present invention.

An alternative "one-pot" method for the preparation of a formula I or Iacompound from a compound of formula V can also be employed. This routeinvolves:

1) The reduction of a formula V compound by diisobutylaluminum hydrideor a similar reducing agent in THF at a temperature below -60° C.

2) Quenching of excess reducing agent with a molar equivalent of aprotic solvent such as methanol or isopropanol.

3) Addition of an aryl Grignard reagent of the formula ##STR26## andwarming to ambient temperature. 4) Standard extractive work-up of thereaction mixture and concentration.

5) Optional treatment of a THF solution of the remnant with a strongacid, such as HCl, for a period of up to 24 h and subsequent basicwork-up. In some cases, the "one-pot" method may provide formula Iaproducts which may be deprotected as described supra. Alternatively, thefinal acid treatment may induce concommitant deprotection and result inthe direct preparation of formula I compounds. Preferred formula Icompounds from this reaction are the same as those preferred formula Icompounds described above, and can be used as pharmaceutically activeagents for the methods herein described, or can be derivatized toprovide other novel compounds of formula I which also are useful for thepresent methods (infra).

Another aspect of the present invention includes compounds of formula II##STR27## wherein B is --CH₂ -- or --CO--

Y, R¹, R², R³, R⁴, n, and W are as defined above;

or a pharmaceutically acceptable salt thereof.

A key intermediate in the preparation of formula II compounds is acompound of formula VI ##STR28## wherein R^(1a), R^(2a), R^(3a), and Yare as defined above. The synthesis of a preferred embodiment of VI, VIain which Y is --CH₂ CH₂ -- is described in Scheme II. ##STR29##

Thus, a readily available tetralone VIIa wherein R^(2a) is as definedabove is condensed with one equivalent of 4-aminophenol, preferably inthe absence of solvent, at a temperature such that the mixture ismolten, usually c. 180° C. under a nitrogen stream. During the course ofthe reaction, additional 4-aminophenol may be added to replace materiallost via sublimation. The resulting imine of formula VIIIa solidifiesupon cooling, and may be optionally recrystallized.

Protection of the hydroxyl group of VIIIa as its silyl derivative VIIIa'is carried out under standard conditions, and the imine is converted toan enamide of formula IXa by acylation with an aroyl halide of formula##STR30## wherein R^(1a) and R^(2a) are as defined above, generally inthe presence of a mild base such as triethylamine and in an inertsolvent such as CH₂ Cl₂ at a temperature between ambient and reflux.

A compound of formula IXa is then photolyzed in a quartz immersion well,using a Hanovia mercury lamp, in a solvent such as ether or benzene, fora period of 4 h to 1 week to provide a compound of formula VIa'. Theprocedure is essentially as described in Journal of the ChemicalSociety, Perkin Transactions I, 762 (1975).

Desilylatlon of a formula VIa' compound under standard conditions thenprovides a compound of formula VIa. For a listing of appropriateconditions see, e.g., Greene and Wuts, Protective Shrouds in OrganicSynthesis, 2nd ed., p. 80, 161 (1991). Preferred formula VI compoundsare those in which R^(1a) and R^(2a) are each individually --H ormethoxy, and R^(3a) is --H. Most preferred is the compound in which bothR^(1a) and R^(2a) are methoxy.

A compound of formula VI is converted to a compound of formula IIb##STR31## wherein R^(1a), R^(2a), R^(3a), R⁴, Y, n, and w are asdescribed above; by the methods described supra for the conversion offormula Ic compounds to formula Ib compounds. For example, a preferredmethod is the Mitsunobu coupling of a formula VI compound with1-(2-hydroxyethyl)pyrrolidine or 1-(2-hydroxyethyl)piperidine.

Once a formula IIb compound is obtained, it may be optionallydeprotected/dealkylated to provide a formula II compound or,alternatively it may be reduced to provide a compound of formula IIc##STR32## wherein R^(1a), R^(2a), R^(3a), R⁴, Y, n, and W are asdescribed above. One method for carrying out this reduction involvesreacting a formula IIa compound with lithium aluminum hydride in aninert solvent such as THF. If the reaction is carried out at ambienttemperature an intermediate product can be isolated which, upon furtherreduction with sodium borohydride in acetic acid is converted to aformula IIc compound. Alternatively, if the reaction is carried out atreflux the desired formula IIc compound can be isolated directly.Compounds of formula IIc can be optionally dealkylated/deprotected toprovide compounds of formula II.

In the preferred case where Y is --CH₂ CH₂ --, i.e. formula IIa##STR33## wherein R^(1a), R^(2a), R^(3a), R⁴, n, and W are as describedabove; it may be desirable to carry out a dehydrogenation reaction, thusproviding a compound of formula IId ##STR34## wherein R^(1a), R^(2a),R^(3a), R⁴, n, and W are as described above. This dehydrogenation may beeffected by various methods known in the art, most preferably viareaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

Alternatively, it may be desirable to perform the dehydrogenation at anearlier stage in the synthesis on a compound of formula VIa' to providea compound of formula VIb: ##STR35## Compounds of formula VIb may thenbe converted to compounds of formula IIe by methods analogous to theconversion of VIa to IIa.

The formula IId compound can be optionally deprotected/dealkylated toprovide a compound of formula II, or alternatively can be reduced, asdescribed supra to provide a compound of formula IIe ##STR36## whereinR^(1a), R^(2a), R^(3a), R⁴, n, and W are as described above. A compoundof formula IIe may then be optionally deprotected/dealkylated to providea compound of formula II.

Collectively, formula IIa-e compounds with their various definedsubstituents, and/or the products of their deprotection as describedabove, are represented as compounds of formula II of the presentinvention.

For example, when R^(1a), R^(2a), and/or R^(3a) of a formula IIecompound are C₁ -C₄ alkyl hydroxy protecting groups, such groups can beremoved via standard dealkylation techniques to prepare an especiallypreferred compound of formula IIe. In the most prefered examples offormula II compounds R¹ and R² are each individually --H, --OH, ormethoxy, Y is --CH═CH--, B is --CH₂ --, n is 1, W is --CH₂ --, and R⁴ is1-piperidinyl or 1-pyrrolidinyl.

An alternative method involves the formation of preferred compounds offormula I or II by replacing the R¹, R², and/or R³ hydroxy groups of aformula I or formula II compound with methoxy. This transformation iscarried out by well known procedures (see, e.g., Greene and Wuts,Protective Groups in Organic Synthesis, 2nd ed., p. (1991)). Anespecially preferred method involves reaction of the mono- or diphenoliccompound with excess diazomethane.

Other preferred compounds of formula I or II are prepared by replacingthe newly formed R¹, R² and/or R³ hydroxy groups of a formula I orformula II compound with a moiety of the formula --O--CO--(C₁ -C₆alkyl), or --O--SO₂ --(C₄ -C₆ alkyl) via well known procedures. See,e.g., U.S. Pat. No. 4,358,593.

For example, when an --O--CO(C₁ -C₆ alkyl) group is desired, thedihydroxy compound of formula I is reacted with an agent such as acylchloride, bromide, cyanide, or azide, or with an appropriate anhydrideor mixed anhydride. The reactions are conveniently carried out in abasic solvent such as pyridine, lutidine, quinoline or isoquinoline, orin a tertiary amine solvent such as triethylamine, tributylamine,methylpiperidine, and the like. The reaction also may be carried out inan inert solvent such as ethyl acetate, dimethylformamide,dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone,methyl ethyl ketone, and the like, to which at least one equivalent ofan acid scavenger (except as noted below), such as a tertiary amine, hasbeen added. If desired, acylation catalysts such as4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, e.g.,Haslam, et al., Tetrahedron, 36:2409-2433 (1980).

The acylation reactions which provide the aforementioned terminal R¹, R²and R³ groups of compounds of formula I or formula II are carried out atmoderate temperatures in the range from about -25° C. to about 100° C.,frequently under an inert atmosphere such as nitrogen gas. However,ambient temperature is usually adequate for the reaction to run.

Such acylations of these hydroxy group also may be performed byacid-catalyzed reactions of the appropriate carboxylic acids in inertorganic solvents or heat. Acid catalysts such as sulfuric acid,polyphosphoric acid, methanesulfonic acid, and the like are used.

The aforementioned R¹, R² and/or R³ groups of formula I or formula IIcompounds also may be provided by forming an active ester of theappropriate acid, such as the esters formed by such known reagents suchas dicyclohexylcarbodiimide, acylimidazoles, nitrophenols,pentachlorophenol, N-hydroxysuccinimide, and 1-hydroxybenzotriazole.See, e.g., Bull, Chem, Soc, Japan, 38:1979 (1965), and Chem, Ber., 788and 2024 (1970).

Each of the above techniques which provide --O--CO-- (C₁ -C₆ alkyl)moieties are carried out in solvents as discussed above. Thosetechniques which do not produce an acid product in the course of thereaction, of course, do not call for the use of an acid scavenger in thereaction mixture.

When a formula I or formula II compound is desired in which the R¹, R²and/or R³ group of a formula I compound is converted to a group of theformula --O--SO₂ --(C₄ -C₆ alkyl) or --O--SO₂ --CF₃, the formula Idihydroxy compound is reacted with, for example, a sulfonic anhydride ora derivative of the appropriate sulfonic acid such as a sulfonylchloride, bromide, or sulfonyl ammonium salt, as taught by King andMonoir, J. Am. Chem. Soc., 97:2566-2567 (1975), or with a reagent suchas N-phenyltrifluoromethanesulfonimide, as taught by Hendrickson andBergeron, Tetrahedron Letters, 4607 (1973). The dihydroxy compound alsocan be reacted with the appropriate sulfonic anhydride, mixed sulfonicanhydrides, or sulfonimides. Such reactions are carried out underconditions such as were explained above in the discussion of reactionwith acid halides and the like.

In the case where R¹, R² and/or R³ of a formula I or formula II compoundhas been converted to --O--SO₂ --CF₃, said derivative can be furtherconverted to a compound of formula I or formula II in which --O--SO₂--CF₃ groups have been replaced by --H. Thus the formula I or formula IItrifluoromethanesulfonate is reduced under conditions described inExample 7, infra, or as taught by Ritter, Synthesis, 735 (1993).

Although the free-base forms of formula I and formula II compounds canbe used in the methods of the present invention, it is occasionallyadvantageous to prepare and use a pharmaceutically acceptable salt form.Thus, the compounds used in the methods of this invention primarily formpharmaceutically acceptable acid addition salts with a wide variety oforganic and inorganic acids, and include the physiologically acceptablesalts which are often used in pharmaceutical chemistry. Such salts arealso part of this invention. Typical inorganic acids used to form suchsalts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric,phosphoric, hypophosphoric, and the like. Salts derived from organicacids, such as aliphatic mono and dicarboxylic acids, phenyl substitutedalkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromaticacids, aliphatic and aromatic sulfonic acids, may also be used. Suchpharmaceutically acceptable salts thus include acetate, phenylacetate,trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate,o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate,phenylbutyrate, b-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate,caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate,glycollate, heptanoate, hippurate, lactate, malate, maleate,hydroxymaleate, malonate, mandelate, mesylate, nicotinate,isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, propiolate, propionate, phenylpropionate, salicylate,sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite,bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate,chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate,methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,p-toluenesulfonate, xylenesulfonate, tartarate, and the like. Apreferred salt is the hydrochloride salt.

The pharmaceutically acceptable acid addition salts are typically formedby reacting a compound of formula I or formula II with an equimolar orexcess amount of acid. The reactants are generally combined in a mutualsolvent such as diethyl ether or ethyl acetate. The salt normallyprecipitates out of solution within about one hour to 10 days and can beisolated by filtration or the solvent can be stripped off byconventional means.

The pharmaceutically acceptable salts generally have enhanced solubilitycharacteristics compared to the compound from which they are derived,and thus are often more amenable to formulation as liquids or emulsions.

The following examples are presented to further illustrate thepreparation of compounds of the present invention. It is not intendedthat the invention be limited in scope by reason of any of the followingexamples.

NMR data for the following Examples were generated on a GE 300 MHz NMRinstrument, and anhydrous acetone-d₆ was used as the solvent unlessotherwise indicated. ##STR37## To tetrahydrofuran 200 mL) containing2-dimethylamino-6-methoxybenzo-[b]-thiophene (cf. U.S. Pat. No.5,420,349)(20.00 g, 96.5 mmol) was added 1N aqueous HCl (200 mL) and theresulting mixture was heated to reflux for 3 h. The mixture was cooled,the layers were separated, and the aqueous layer was extracted withdichloromethane (300 mL). The combined organic layers washed with water(250 mL), dried (MgSO₄), filtered and concentrated to give crudeproduct, which was recrystallized from 3A-ethanol, and dried in vacuo atroom temperature to afford the title compound (13.89 g, 77.0 mmol, 80%):mp 80-82° C.; IR (KBr) 1713, 1605, 1485, 1287, 1015, 865, 813 cm⁻¹ ; ¹ HNMR (DMSO-d₆) δ 7.22 (d, 1H, J=8.4 Hz), 7.11 (s, 1H), 6.78 (d, 1 HTJ=8.4 Hz), 4.06 (s, 2H), 3.71 (s, 3H); ¹³ C NMR (DMSO-d₆) δ 203.5,159.0, 136.9, 125.6, 124.6, 112.3, 108.4, 55.3, 46.2. Anal. Calcd. forC₉ H₈ O₂ S: C, 59.98; H, 4.47; S, 17.78. Found: C, 60.19; H, 4.57; S,18.03. ##STR38## To a stirred solution of 6-methoxythianaphthen-2-one(see Docket B-9459) (20 g, 111 mmol) in a mixture of ethanol (100 mL)and methylene chloride (50 mL) was added 4-methoxysalicylaldehyde (17.5g, 115 mmol) followed by triethyiamine (567 mg, 784 mL, 5.6 mmol) atroom temperature. After 30 min, a solid began to precipitate andstirring was continued overnight. The mixture was then diluted with coldhexane (1 L) and filtered to yield 28.7 g (82%) of the title product asan off-white solid, pure by ¹ H-NMR analysis. An analytical sample wasobtained by recrystallization from toluene as light yellow crystals, mp157-165d° C.: ¹ H-NMR (300 MHz, CDCl₃) d 7.33 (d, J=8.6 Hz, 1H), 7.31(d, J=8.1 Hz, 1H), 6.75 (d, J 2.4 Hz, 1H), 6.70 (m, 2H), 6.60 (d, J=2.5Hz, 1H), 5.22 (d, J=7.2 Hz, 1H), 4.33 (d, J=7.2 Hz, 1H), 3.79 (s, 3H),3.76 (s, 3H); IR (CHCl₃) 1759 cm⁻¹ ; MS (FD) m/e 314 (M+); Anal. calc'd.for C₁₇ H₁₄ O₄ S: C, 64.95; H, 4.50. Found: C, 65.01; H, 4.58. ##STR39##A mixture of the product of Preparation 2 (4.5 g, 14.3 mmol) and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (3.4 g, mmol) indichloroethane (100 mL) was heated briefly to 80° C., inducing theformation of a precipitate. The mixture was filtered hot, rinsing theprecipitate with methylene chloride, and the mother liquor concentratedin vacuo. The remnant was dissolved in hot methylene chloride, filteredto remove residual hydroquinone, and reconcentrated. The product wasrecrystallized from toluene to provide 3.94 g (88%) of the title productas white needles, mp 220-221° C.: ¹ H-NMR (acetone-d₆ /DMSO-d₆) d 8.41(d, J=8.9 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.74 (d, J=2.3 Hz, 1H), 7.20(dd, J=8.9, 2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.6, 2.4Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H); IR (KBr) 1717 cm⁻¹ ; MS (FD+) m/e312 (M+); Anal. calc'd. for C₁₇ H₁₂ O₄ S: C, 65.37; H, 3.88. Found: C,65.51; H, 3.90. ##STR40## To a mechanically stirred slurry of theproduct of Preparation 2 (12 g, 38.4 mmol) in methylene chloride (220mL) was added ethanethiol (11.9 g, 13.4 mL, 192 mmol) followed byaluminum chloride (38.4 g, 288 mmol), portionwise. The reaction mixturewas stirred at ambient temperature for 5 h, then cooled to 0° C. andquenched cautiously with tetrahydrofuran (THF) (250 mL) followed bysaturated sodium bicarbonate (250 mL). The mixture was diluted with THF(1 L), the layers separated, and the aqueous layer was washed with THF(200 mL). The combined organic layers were dried (sodium sulfate) andconcentrated to yield 11.1 g (102%) of crude diphenol as a yellow solid,which was used without further purification.

The crude product was slurried in methylene chloride (220 mL) andtreated with triethylamine (20.2 g, 28 mL, 200 mmol) andtert-butyldimethylsilyl chloride (20.3 g, 134.4 mmol). The mixture wasstirred at ambient temperature for 5 h, during which it slowly becamehomogeneous. After dilution with hexane (600 mL), the mixture was washedwith brine (600 mL) and the aqueous layer was extracted with hexane (300mL). The combined organic layers were dried (sodium sulfate),concentrated, and the residue recrystallized from hexane to provide 18.0g (91%) of the title compound as a fluffy white solid, mp 142-144° C.: ¹H-NMR (300 MHz, CDCl₃, d 8.50 (d, J=8.7 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H),7.32 (d, J=2.1 Hz, 1H), 7.05 (dd, J=8.7, 2.1 Hz, 1H), 6.92 (d, J=2.2 Hz,1H), 6.84 (dd, J=8.4, 2.2 Hz, 1H), 1.01 (s, 9H), 1.00 (s, 9H), 0.27 (s,6H), 0.25 (s, 6H); ¹³ C-NMR (75 MHz, DMSO-d₆) d 158.4, 157.0, 154.6,152.7, 149.6, 138.5, 130.5, 125.2, 124.6, 120.0, 117.6, 116.3, 112.7,111.3, 108.0, 25.6, 25.6, 18.2, 18.2, -4.4, -4.4; IR (CHCl₃) 1717 cm⁻¹ ;MS (FD) m/e 512 (M+); Anal. calc'd. for C₂₇ H₃₆ O₄ SSi₂ : C, 63.24; H,7.08. Found: C, 63.45; H, 7.36. ##STR41## A solution of the product fromPreparation 3 (2.0 g, 3.9 mmol) in toluene (200 mL) was cooled to -92°C. and treated dropwise with a 1.0 M toluene solution ofdiisobutylaluminum hydride (11.3 mL, 11.3 mmol) at a rate maintainingthe internal temperature below -89° C. The mixture was stirred forapproximately 3 h, as the temperature gradually rose to -77° C., thenquenched with methanol (5 mL) and 10% aqueous citric acid (50 mL). Afterdilution with methylene chloride (200 mL), the mixture was washed withsaturated potassium sodium tartrate 100 mL), and the aqueous layer wasextracted with methylene chloride (2×200 mL). The combined organiclayers were washed with brine (300 mL) and the brine wash was furtherextracted with methylene chloride (100 mL). The organic layers weredried (sodium sulfate), concentrated, and the remnant chromatographed(silica gel, 1-15% ethyl acetate/hexane) to yield 360 mg (18%) ofstarting material, 1.21 g (60%, 74% based on recovered startingmaterial) of the titled compound as a white crystalline solid(analytical sample recrystallized from hexane/ethyl acetate, mp 162-164°C.): ¹ H NMR (300 MHz) d 7.70 (d, J=9.0 Hz, 1H), 7.46 (d, J=2.1 Hz, 1H),7.29 (d, J=8.1 Hz, 1H), 7.00 (dd, J=8.5, 1.8 Hz, 1H), 6.85 (br s, 1H),6.6 (m, 2H), 6.39 (br s, 1H), 1.01 (s, 9H), 1.00 (s, 9H), 0.25 (s, 6H),0.25 (s, 6H) ¹³ C NMR (125 MHz) d 156.9, 153.3, 151.7, 139.9, 131.9,124.5, 123.9, 121.7, 118.8, 113.7, 113.1, 112.7, 108.7, 90.7, 25.1,25.1, 17.9, -5.2, -5.2; IR (CHCl₃) 3540 cm⁻¹ ; MS (FD+) m/e 514 (M+);Anal. calc'd. for C₂₇ H₃₈ O₄ SSi₂ : C, 62.98; H, 7.45. Found: C, 63.25;H, 7.68, and 260 mg (13%, 16% based on recovered starting material ofthe diol below ##STR42## as an amorphous solid: ¹ H NMR (300 MHz, CDCl₃)d 7.73 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.16 (d, J=8.2 Hz,1H), 6.98 (dd, J=8.7, 2.0 Hz, 1H), 6.5 (m, 3H), 6.30 (br s, 1H), 4.71(s, 2H), 1.01 (s, 9H), 1.00 (s, 9H), 0.22 (s, 6H), 0.19 (s, 6H); IR(CHCl₃) 3600, 3510 cm⁻¹ ; MS (FD+) m/e 516 (M+); Anal. calc'd. for C₂₇H₄₀ O₄ SSi₂ : C, 62.73; H, 7.82. Found: C, 62.49; H, 7.83. ##STR43## Toa solution of the product of Preparation 4 (4.52 g, 8.78 mmol) andphenol (4.13 g, 43.9 mmol) in methylene chloride (100 mL) was addedanhydrous magnesium sulfate (4.5 g) and the resultant slurry was stirredfor 4 h at ambient temperature. The mixture was filtered andconcentrated and the residue dissolved in chlorobenzene andreconcentrated in vacuo at approximately 70° C. The residue was thendissolved in methylene chloride (300 mL), washed with saturated sodiumcarbonate (3×300 mL) and water (2×300 mL), dried (sodium sulfate), andconcentrated to yield 5.16 g (99%) of the title compound as an amorphoussolid which was used without further purification: ¹ H NMR (300 MHz) d7.67 (d, J=8.7 Hz, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.4-7.5 (m, 4H), 7.23(d, J=8.4 1H), 7.08 (t, J=7.2 Hz, 1H), 6.99 (dd, J=8.7, 2.1 Hz, 1H),6.67 (dd, J=8.4, 2.3 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 0.99 (s, 9H), 0.96(s, 9H), 0.24 (s, 6H), 0.21 (s, 6H); ¹³ C NMR (125 MHz) d 156.9, 153.3,151.7, 139.9, 131.9, 124.5, 123.9, 121.7, 118.8, 113.7, 113.1, 112.7,108.7, 90.7, 25.1, 25.1, 17.9, -5.2, -5.2; MS (FD+) m/e 590 (M+); Anal.calc'd. for C₃₃ H₄₂ O₄ SSi₂ : C, 67.06; H, 7.18. Found: C, 66.78; H,6.96. ##STR44## To a solution of the product of Preparation 5 (4.0 g,6.7 mmol) in toluene (100 mL) at 0° C. was added a 0.5 M THF solution of4-[2-(1-piperidinyl)ethoxy]phenylmagnesium bromide (prepared from thecorresponding bromobenzene and magnesium turnings, catalyzed by iodinein THF, 27 mL, 13.5 mmol). The mixture was allowed to warm to roomtemperature and stirred for 1.5 h. After quenching with water (300 mL),the mixture was extracted with ethyl acetate (2×300 mL), and the organiclayer was dried (sodium sulfate) and concentrated. The residue waspurified via chromatography (silica gel, 3:1 hexane:ethyl acetate, 0.1%ammonium hydroxide) to give 3.85 g (82%) of the title compound as acolorless, gummy solid: ¹ H NMR (300 MHz) d 7.45 (s, 1H), 7.2-7.3 (m,4H), 6.8-6.9 (m, 3H), 6.68 (s, 1H), 6.51 (d, J=8.1 Hz, 1H), 6.36 (s,1H), 4.01 (t, J=6.0 Hz, 2H), 2.62 (t, J=6.0 Hz, 2H), 2.41 (m, 4H),1.4-1.6 (m, 4H), 1.3-1.4 (m, 2H), 0.99 (s, 9H), 0.96 (s, 9H), 0.22 (s,6H), 0.20 (s, 6H); ¹³ C NMR (125 MHz) d 160.3, 157.9, 154.0, 153.5,141.0, 132.8, 132.6, 130.1, 129.8, 126.1, 124.8, 122.7, 119.4, 115.3,114.5, 114.2, 114.0, 109.4, 78.2, 66.9, 58.5, 55.6, 26.8, 26.0, 26.0,25.0, 18.7, -4.3, -4.3; MS (FD) m/e 702 (M+); Anal. calc'd. for C₄₀ H₅₅NO₄ SSi₂ : C, 68.43; H, 7.90; N, 2.00. Found: C, 68.58; H, 8.00; N, 9.26

EXAMPLE 1 ##STR45## To a solution of the Preparation 6 product (3.85 g,5.5 mmol) in THF (150 mL), was added a 1.0 M THF solution oftetra-n-butylammonium fluoride (TBAF) (27.4 mL, 27.4 mmol). The solutionwas stirred at ambient temperature for 2 h, then diluted with ethylacetate (300 mL) and washed with saturated ammonium chloride (100 mL).The aqueous layer was washed with ethyl acetate (150 mL), and thecombined organic layers were washed with saturated sodium bicarbonate(300 mL), dried (sodium sulfate), and concentrated. The remnant waspurified by chromatography (silica gel, 1:1 hexane:ethyl acetate, 10%methanol, 0.1% ammonium hydroxide) to give 2.35 g (90%) of the titledproduct as a red foam. Crystallization from methanol gave an off-whitepowder, mp 242-245d° C.: ¹ H NMR (300 MHz) d 8.58 (br s, 2H), 7.35 (d,J=2.1 Hz, 1H), 7.26 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.2 Hz, 1H), 7.16 (d,J=8.6 Hz, 1H), 6.84 (d, J=8.5 Hz, 2H), 6.80 (m, J=2.2 Hz, 1H), 6.63 (s,1H), 6.46 (dd, J=8.2, 2.2 Hz, 1H), 6.35 (d, J=2.3 Hz, 1H), 4.02 (t,J=6.0 Hz, 2H), 2.63 (t, J=6.0 Hz, 2H), 2.42 (m, 4H), 1.4-1.6 (m, 4H),1.3-1.4 (m, 2H); ¹³ C NMR (125 MHz, dimethylformamide-d₇) d 160.2,159.9, 156.4, 153.2, 140.8, 132.8, 130.9, 129.6, 125.3, 124.6, 122.5,115.2, 115.1, 112.2, 109.6, 108.8, 108.7, 104.5, 77.6, 66.6, 58.3, 55.3,26.5, 24.8; HRMS (FAB+) m/e calc'd. for C₂₈ H₂₈ NO₄ S 474.1739 (MH+),found 474.1726; Anal. calc'd. for C₂₈ H₂₇ NO₄ S.0.8H₂ O: C, 68.90; H,5.92; N, 2.87. Found: C, 68.88; H, 5.76; N , 2.86. EXAMPLE 2 ##STR46## Asolution of the product of Example 1 (300 mg, 0.633 mmol) in methanol(75 mL) was treated with a solution of diazomethane in ether/ethanol(approximately 16 mmol) at ambient temperature. The mixture was stirreduntil gas evolution ceased, nitrogen was bubbled through for 10 min toremove excess diazomethane, and the mixture was concentrated. Radialchromatography of the residue (1:1 hexane:ethyl acetate, 2% methanol,under an ammonia atmosphere) provided 118 mg (37%) of the title compoundas white crystals, mp 134-36: ¹ H NMR (300 MHz) d 7.51 (d, J=2.2 Hz,1H), 7.2-7.4 (m, J=8.6 Hz, 4H), 6.86 (m, 3H), 6.70 (s, 1H), 6.55 (dd,J=8.4, 2.3 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.83(s, 3H), 3.74 (s, 3H), 2.62 (t, J=6.0 Hz, 2H), 2.40 (m, 4H), 1.4-1.6 (m,4H), 1.3-1.4 (m, 2H); ¹³ C NMR (125 MHz, CDCl₃) d 160.8, 159.2, 157.1,152.6, 140.3, 131.6, 131.3, 130.5, 129.1, 124.3, 124.0, 121.7, 114.6,114.0, 112.8, 107.6, 105.7, 102.3, 77.9, 65.8, 57.8, 55.5, 55.2, 54.9,25.9, 24.1; MS (FD+) m/e 501 (M+); Anal. calc'd. for C₃₀ H₃₁ NO₄ S: C,71.83; H, 6.23; N, 2.79. Found: C, 71.53; H, 6.20; N, 2.84. EXAMPLE 3##STR47## To a solution of the product of Example 1 (200 mg, 0.42 mmol)in methylene chloride (25 mL) at room temperature was addedtriethylamine (0.18 mL, 1.27 mmol) followed by benzoyl chloride (0.15mL, 1.27 mmol) via syringe over 10 minutes. The reaction mixture wasstirred for 16 hours and then washed with saturated sodium bicarbonate(25 ml) followed by water (25 ml). The organic layer was dried (sodiumsulfate) and concentrated, and the residue was purified by radialchromatography (silica gel, 12:12:1 ethyl acetate:hexanes:methanol underan ammonia atmosphere) to afford 200 mg (69%) of the title compound as atan solid: ¹ H NMR (300 MHz, DMSO-d₆) d 8.1-8.2 (m, 5H), 7.5-7.8 (m,8H), 7.2-7.3 (m, 3H), 6.9-7.0 (m, 5H), 4.00 (t, J=5.5 Hz, 2H), 2.60 (t,J=4.8 Hz, 2H), 2.38 (m, 4H), 1.4-1.5 (m, 4H), 1.3-1.4 (m, 2H); HRMS(FAB+) m/e calc'd. for C₄₂ H₃₆ NO₆ S 682.2263 (MH+), found 682.2286.EXAMPLE 4 ##STR48## According to the procedure of Example 2, the productof Example 1 (200 mg, 0.42 mmol) was reacted with triethylamine (0.18mL, 1.27 mmol) and pivaloyl chloride (0.16 mL, 1.27 mmol) in methylenechloride (25 mL) to afford 190 mg (70%) of the title compound as a whitefoam: ¹ H NMR (300 MHz, CDCl₃) d 7.58 (d, J=1.7 Hz, 1H), 7.35 (d, J=8.1Hz, 1H), 7.26 (d, J=9.6 Hz, 2H), 7.14 (d, J=8.7 Hz, 1H), 6.93 (dd,J=8.8, 2.1 Hz, 1H), 6.83 (d, J=8.6 Hz, 2H), 6.70 (dd, J=4.3, 2.1 Hz,1H), 6.63 (s, 2H), 4.13 (t, J=5.4 Hz, 2H), 2.83 (m, 2H), 2.58 (m, 4H),1.66 (m, 4H), 1.46 (m, 2H), 1.37 (s, 9H), 1.33 (s, 9H); MS (FD+) m/e 641(M+); HRMS (FAB+) m/e calc'd. for C₃₈ H₄₄ NO₆ S 642.2889 (MH+), found642.2848; Anal.calc'd. for C₃₈ H₄₃ NO₆ S: C, 71.11; H, 6.75; N, 2.18.Found: C, 71.86; H, 6.49; N, 2.09. EXAMPLE 5 ##STR49## According to theprocedure of Example 2, the product of Example 1 (200 mg, 0.42 mmol) wasreacted with triethylamine (0.18 mL, 1.27 mmol) and n-butanesulfonylchloride (0.17 mL, 1.27 mmol) in methylene chloride (25 mL) to afford120 mg (40%) of the title compound as a clear brown gum: ¹ H NMR (300MHz, CDCl₃) d 7.7, (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.29 (d, J=9.5 Hz,2H), 7.11 (s, 2H), 6.8-6.9 (m, 4H), 6.63 (s, 1H), 4.08 (t, J=5.4 Hz,2H), 3.2-3.2 (m, 4H), 2.77 (t, J=5.4 Hz, 2H), 2.51 (m, 4H),1.9-2.0 (m,4H) 1.4-1.6 (m, 10H), 0.9-1.0 (m, 6H); HRMS (FAB+) m/e calc'd. for C₃₈H₄₄ N₀₈ S₃ 714.2229 (MH+), found 714.2206. EXAMPLE 6 ##STR50## To asolution of the product of Example 1 (500 mg, 1.06 mmol) in THF (25 mL)containing dimethylformamide (2 mL) at room temperature was addedtriethylamine (0.64 g, 0.69 mL, 6.36 mmol) followed byN-phenyltrifluoromethanesulfonimide (0.83 g, 2.33 mmol). The reactionmixture was stirred for 12 hours, warmed to 60° C., and additionalN-phenyltrifluoromethanesulfonimide (0.30 g, 0.85 mmol) was added. After30 min, the reaction mixture was cooled to ambient temperature andconcentrated, and the residue was purified by radial chromatography(silica gel, 1:1 hexane:ethyl acetate, 1% methanol under an ammoniaatmosphere) to afford 780 mg (100%) of the title compound as a whitefoam: ¹ H NMR (300 MHz, methanol-d₄) d 7.63 (d, J=8.8 Hz, 1H), 7.56 (d,J=2.5 Hz, 1H), 7.13 (dd, J=8.8, 2.7 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H),6.80 (d, J=8.9 Hz, 2H), 6.49 (d, J=2.5 Hz, 1H), 6.39 (d, J=8.7 Hz, 1H),6.05 (dd, J=8.7, 2.6 Hz, 1H), 4.00 (t, J=5.5 Hz, 2H), 2.67 (m, 2H), 2.45(m, 4H), 1.4-1.6 (m, 4H), 1.3-1.4 (m, 2H); ¹³ C NMR (125 MHz) d 159.8,152.8, 150.2, 146.9, 140.4, 136.6, 130.5, 129.2, 127.3, 125.3, 123.4,119.2, 118.9, 116.3, 114.7, 114.6, 110.4, 77.7, 66.0, 57.6, 54.7, 25.8,24.0; MS (FD) m/e 737 (M+); Anal. calc'd for C₃₀ H₂₅ F₆ NO₈ S₃ : C,48.84; H, 3.42; N, 1.90. Found: C, 49.05; H, 3.71; N, 1.72. EXAMPLE 7##STR51## A solution of the product of Example 6 (780 mg, 1.06 mmol),palladium(II) acetate (42 mg, 0.19 mmol),1,2-bis(diphenylphosphinopropane (149 mg, 0.36 mmol), formic acid (0.6mL), and triethylamine (3.0 mL) in anhydrous dimethylformamide (40 mL)was stirred at ambient temperature for 4 d. After concentration, theresidue was subjected chromatography (silica gel, 1:1hexane:ethylacetate, 2-10% methanol, 0.1% ammonium hydroxide). Productcontaining fractions were concentrated, partitioned between methylenechloride (100 mL) and saturated sodium bicarbonate (100 mL), and theaqueous layer extracted with methylene chloride (50 mL). The combinedorganic extracts were dried (sodium sulfate), concentrated, and theresidue purified by chromatography (silica gel, 1:1 hexane:ethylacetate,2-10% methanol, 0.1% ammonium hydroxide) to give 267 mg (57%) of thetitle compound as an oil which gave a white, crystalline solid, mp 107°C., upon trituration with ether/hexane: ¹ H NMR (300 MHz, CDCl₃) d 7.86(d, J=7.4 Hz, 1H), 7.40 (m, 1H) 7.1-7.3 (m, 6H), 6.97 (t, J=7.3 Hz, 1H),6.89 (d, J=8.1 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.66 (s, 1H), 4.07 (t,J=6.1 HZ, 2H), 2.75 (t, J=6.1 Hz, 2H), 2.49 (m, 4H), 1.5-1.7 (m, 4H),1.4-1.5 (m, 2H); ¹³ C NMR (125 MHz, CDCl₃) d 159.1, 151.6, 139.3, 137.1,133.0, 131.5, 129.8, 129.1, 126.8, 124.6, 124.4, 123.7, 122.6, 121.5,121.5, 119.3, 116.9, 114.6, 77.6, 65.7, 57.7, 54.9, 25.8, 24.0; MS (FD+)m/e 441 (M+); Anal. calc'd for C₂₈ H₂₇ NO₂ S: C, 76.15; H, 6.17; N,3.17. Found: C, 75.93; H, 6.44; N, 3.01. ##STR52## To a solution of theproduct of Preparation 5 (3.0 g, 5.08 mmol) in toluene (150 mL) at 0° C.was added a 0.4 M THF solution of 4-(trimethylsilyloxy)phenylmagnesiumbromide (prepared from the corresponding bromobenzene and magnesiumturnings, catalyzed by iodine in THF, 25.4 mL, 10.16 mmol). The mixturewas allowed to warm to room temperature and stirred for 1.5 h. Afterdilution with ether (250 mL), the mixture was quenched with saturatedammonium chloride (250 mL) and the organic layer was dried (sodiumsulfate) and concentrated. The residue was slurried in methanol (100 mL)and ether was added until the mixture was homogeneous. The solution wascooled to 0° C. and treated with anhydrous potassium carbonate (3 g) for15 min. After dilution with ether (250 mL), the mixture was filteredthrough Celite, washed with saturated ammonium chloride, and the aqueouslayer was extracted with additional ether (100 mL). The combined organiclayers were dried (sodium sulfate), concentrated, and the residuepurified by chromatography (silica gel, 10:1 hexane:ethyl acetate).Recrystallization from hexane provided 2.6 g (87%) of the title compoundas a light pink solid, mp 174-175° C.: ¹ H NMR (300 MHz) d 8.49 (s, 1H),7.44 (d, J=2.2 Hz, 1H), 7.3-7.4 (m, 4H), 6.83 (dd, J=8.7, 2.2 Hz, 1H),6.76 (d, J=8.5 Hz, 2H), 6.65 (s, 1H), 6.50 (dd, J=8.2, 2.3 Hz, 1H), 6.36(d, J=2.3 Hz, 1H), 0.98 (s, 9H), 0.95 (s, 9H), 0.21 (s, 6H), 0.20 (s,6H); ¹³ C NMR (125 MHz) d 158.7, 157.8, 153.9, 153.5, 140.9, 132.7,131.6, 131.1, 129.9, 126.1, 124.7, 122.7, 119.3, 116.1, 114.4, 114.0,113.9, 109.3, 78.3, 26.0, 25.9, 18.7, -4.3; IR (CHCl₃) 3590, 3310 cm⁻¹ ;MS (FD+) m/e 590 (M+); Anal. cald'd. for C₃₃ H₄₂ 04SSi₂ : C, 67.07; H,7.16. Found: C, 66.79; H, 7.05. ##STR53## A toluene solution of theproduct of Preparation 7 (400 mg, 0.68 mmol), triphenylphosphine (708mg, 2.7 mmol), and 1-(2-hydroxyethyl)pyrrolidine (390 mg, 396mL, 3.39mmol) was treated with diethyl azodicarboxylate (DEAD) (470 mg, 425mL,2.7 mmol) at room temperature and stirred for 2 h. The mixture was thendiluted with ether (100 mL), washed with saturated ammonium chloride(100 mL), and the aqueous layer washed with additional ether (50 mL).The combined organic layers were dried (sodium sulfate), concentrated,and the residual triphenylphosphine oxide precipitated from hexane. Thehexane mother liquor was concentrated and the residue purified bychromatography (silica gel, 1:1 hexane:ethyl acetate, 3-5% methanol,0.1% ammonium hydroxide) to give 359 mg (77%) of the title compound as acolorless oil: ¹ H NMR (300 MHz) d 7.45 (d, J=2.1 Hz, 1H), 7.28 (d,J=8.6 Hz, 2H), 7.22 (m, 2H), 6.85 (d, 8.6 Hz, 2H), 6.83 (dd, J=8.6, 2.3Hz, 1H), 6.68 (s, 1H), 6.50 (dd, J=8.3, 2.2 Hz, 1H), 6.36 (d, 2.2 Hz,1H), 4.03 (t, J=6.0 Hz, 2H), 2.77 (t, J=6.0 Hz, 2H), 2.50 (m, 4H), 1.67(m, 4H), 0.98 (s, 9H), 0.95 (s, 9H), 0.21 (s, 6H), 0.20 (s, 6H); ¹³ CNMR (125 MHz) d 160.1, 157.8, 153.9, 153.4, 140.9, 132.7, 132.5, 131.1,129.8, 125.9, 124.7, 122.6, 119.3, 115.1, 114.4, 114.1, 113.9, 109.4,78.1, 57.7, 55.2, 54.9, 26.0, 25.9, 24.0, 18.6, -4.3; MS (FD+) m/e 687(M+); Anal. calc'd. for C₃₉ H₅₃ NO₄ SSi₂ :

C, 68.06; H, 7.78; N, 2.04. Found: C, 67.94; H, 7.61; N, 2.21.

EXAMPLE 8 ##STR54## By the procedure described for Example 1, theproduct of Preparation 8 (331 mg, 0.48 mmol) was reacted with 1.0 M TBAFin THF (2.4 mmol) to give, after radial chromatography (silica gel, 1:1hexane:ethyl acetate, 30% methanol, under an ammonia atmosphere) 200 mg(91%) of the title compound as a white solid, mp 237-240d° C.: ¹ H NMR(300 MHz, dimethylformamide-d₇) d 10.05 (br, 2H), 7.45 (d, J=2.0 Hz,1H), 7.30 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.6 Hz, 1H), 7.19 (d, J=8.2 Hz,1H), 6.91 (d, J=8.7 Hz, 2H), 6.86 (dd, J=8.9, 2.2 Hz, 1H), 6.74 (s, 1H),6.51 (dd, J=8.2, 2.1 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 4.14 (t, J=5.6 Hz,2H), 2.96 (t, J=5.5 Hz, 2H), 2.6-2.8 (m, 4H), 1.6-1.8 (m, 4H); ¹³ C NMR(125 MHz, dimethylformamide-d₇) d 160.2, 159.6, 156.4, 153.2, 140.8,133.0, 130.8, 129.6, 125.2, 124.6, 122.4, 115.3, 115.1, 112.2, 109.7,108.8, 104.5, 77.6, 66.8, 54.8, 54.7, 23.8; IR (KBr) 3286 cm⁻¹ ; HRMS(FAB+) m/e calc'd. for C₂₇ H₂₆ NO₄ S 460.1583 (MH+), found 460.1572;Anal. calc'd. for C₂₇ H₂₅ NO₄ S.0.5H₂ O: C, 69.20; H, 5.60; N, 2.99.Found: C, 69.13; H, 5.31; N, 2.58. ##STR55##

By the method described in Preparation 8, the product of Preparation 7(450 mg, 0.76 mmol), triphenylphosphine (799 mg, 3.1 mmol), andN,N-dimethylethanolamine (340 mg, 383 mL, 3.81 mmol) were reacted withdiethyl azodicarboxylate (DEAD) (531 mg, 480mL, 3.1 mmol) in toluene (30mL). Chromatography 2H), 2.30 (s, 6H); ¹³ C NMR (125 MHz) d 160.0,159.8, 156.0, 153.5, 141.1, 133.0, 131.4, 130.2, 129.8, 125.3, 124.8,122.6, 115.3, 115.2, 112.7, 109.7, 109.0, 104.8, 78.0, 66.6, 58.6, 45.8;IR (KBr) 3300 cm⁻¹ ; HRMS (FAB+) m/e calc'd. for C₂₅ H₂₄ NO₄ S 434.1426(MH+), found 434.1440; Anal. calc'd. for C₂₅ H₂₃ NO₄ S.0.4CCl₄ : C,61.62; H, 4.69; N, 2.83. Found: C, 60.93; H, 4.73; N, 2.95. ##STR56## Bythe method described in Preparation 8, the product of Preparation 7 (450mg, 0.76 mmol), triphenylphosphine (799 mg, 3.1 mmol), and1-(2-hydroxyethyl)-2-pyrrolidinone (492 mg, 431 mL, 3.81 mmol) werereacted with diethyl azodicarboxylate (DEAD) (531 mg, 480 mL, 3.1 mmol)in toluene (30 mL). Chromatography (silica gel, 1:1 hexane:ethylacetate) provided 368 mg (69%) of the title compound as a white foam: ¹H NMR (300 MHz) d 7.45 (d, J=2.1 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.23(d, J=8.2 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 6.88 (m, 3H), 6.69 (s, 1H),6.51 (dd, J=8.5, 2.5 Hz, 1H), 6.36 (d, 2.3 Hz, 1H), 4.05 (t, J=5.4 Hz,2H), 3.54 (t, J=5.4 Hz, 2H), 3.46 (t, J=7.0 Hz, 2H), 2.15 (t, J=8.0 Hz,2H), 1.91 (m, 2H), 0.98 (s, 9H), 0.95 (s, 9H), 0.21 (s, 6H), 0.20 (s,6H); ¹³ C NMR (125 MHz) d 175.0, 160.1, 158.1, 154.2, 153.6, 141.2,133.2, 133.0, 131.4, 130.1, 126.2, 125.0, 122.9, 119.6, 115.5, 114.6,114.4, 114.2, 109.6, 78.3, 67.0, 48.7, 42.7, 31.2, 26.2, 26.2, 18.9,-4.1; IR (CHCl₃ (1673 cm⁻¹ ; HRMS (FAB+) m/e calc'd. for C₃₉ H₅₁ NO₅SSi₂ 701.3027 (M+), found 701.3039.

EXAMPLE 10 ##STR57## By the procedure described for Example 1, theproduct of Preparation 10 (331 mg, 0.47 mmol) was reacted with 1.0 MTBAF in THF (2.4 mmol) to give, after radial chromatography (silica gel,1:1 hexane:ethyl acetate, 20% methanol, under an ammonia atmosphere) andrecrystallization from acetone 161 mg (72%) of the title compound as ared solid, mp 150-160d° C.: ¹ H NMR (300 MHz, methanol-d₄) d 7.21 (m,3H), 7.11 (d, J=8.3 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 6.80 (d, J=8.6 Hz,2H), 6.71 (dd, J=8.6, 2.2 Hz, 1H), 6.51 (s, 1H), 6.37 (dd, J=8.2, 2.3Hz, 1H), 6.25 (d, J=2.3 Hz, 1H), 4.04 (t, J=5.2 Hz, 2H), 3.57 (t, J=5.2Hz, 2H), 3.48 (t, J=7.1 Hz, 2H), 2.28 (t, J=8.1 Hz, 2H), 1.91 (quintet,J=7.5 Hz, 2H); ¹³ C NMR (125 MHz, methanol-d₄) d 178.0, 160.2, 160.0,156.2, 153.9, 141.7, 133.7, 131.9, 130.9, 130.3, 125.6, 125.0, 122.7,115.6, 115.1, 113.4, 109.8, 109.0, 104.9, 78.6, 66.6, 43.4, 31.8, 30.7,13.9; IR (CHCl₃) 1680 cm⁻¹ ; MS (FD+) m/e 474 (MH+); Anal. calc'd. forC₂ 7H₂₃ NO₅ S.(CH₃)2CO: C, 67.77; H, 5.51; N, 2.64. Found: C, 67.92; H,5.56; N, 2.59. ##STR58## By the method described in Preparation 8, theproduct of Preparation 7 (500 mg, 0.85 mmol), triphenylphosphine (892mg, 3.4 mmol), and N,N-diethylethanolamine (496 mg, 438 mL, 4.23 mmol)were reacted with diethyl azodicarboxylate (DEAD) (592 mg, 535 mL, 3.4mmol) in toluene (35 mL). Chromatography (silica gel, 3:1 hexane:ethylacetate, 0.1% ammonium hydroxide) provided 540 mg (92%) of the titlecompound as a colorless oil: ¹ H NMR (300 MHz) d 7.46 (d, J=2.5 Hz, 1H),7.3-7.4 (m, 4H), 6.86 (m, 3H), 6.69 (s, 1H), 6.51 (dd, J=8.3, 2.3 Hz,1H), 6.37 (d, 2.2 Hz, 1H), 3.98 (t, J=6.3 Hz, 2H), 2.77 (t, J=6.3 Hz,2H), 2.54 (q, J=7.1 Hz, 4H), 0.99 (s, 9H), 0.97 (t, J=7.0 Hz, 6H), 0.96(s, 9H), 0.22 (s, 6H), 0.21 (s, 6H); ¹³ C NMR (125 MHz) d 160.0, 157.5,153.7, 153.3, 140.8, 132.6, 132.3, 131.1, 129.7, 125.7, 124.6, 122.5,119.2, 115.0, 114.2, 113.9, 113.7, 109.3, 78.1, 67.2, 52.3, 48.1, 26.0,26.0, 18.6, 12.5, -4.3; MS (FD+) m/e 689 (M+); ##STR59## By the methoddescribed in Preparation 8, the product of Preparation 7 (500 mg, 0.85mmol), triphenylphosphine (892 mg, 3.4 mmol), and1-(2-hydroxyethyl)morpholine (555 mg, 512 mL, 4.23 mmol) were reactedwith diethyl azodicarboxylate (DEAD) (592 mg, 535 mL, 3.4 mmol) intoluene (35 mL). Chromatography (silica gel, 3:1 hexane:ethyl acetate,0.1% ammonium hydroxide) provided 569 mg (95%) of the title compound asa pink foam: ¹ H NMR (300 MHz) d 7.46 (d, J=2.1 Hz, 1H), 7.2-7.3 (m,4H), 6.86 (m, 3H), 6.70 (s, 1H), 6.51 (dd, J=8.2, 2.3 Hz, 1H), 6.37 (d,2.7 Hz, 1H), 4.04 (t, J=5.8 Hz, 2H), 3.57 (t, J=4.5 Hz, 2H), 2.69 (t,J=5.7 Hz, 2H), 2.47 (m, 4H), 0.99 (s, 9H), 0.96 (s, 9H), 0.22 (s, 6H),0.21 (s, 6H); ¹³ C NMR (125 MHz) d 159.8, 157.6, 153.7, 153.2, 140.8,132.5, 132.5, 131.1, 129.7, 125.8, 124.6, 122.5, 119.2, 115.1, 114.2,114.0, 113.8, 109.3, 78.2, 67.0, 66.2, 57.9, 54.6, 26.0, 25.9, 18.6,-4.3; MS (FD+) m/e 703 (M+); ##STR60## Coumestrol (10 g, 37.3 mmol) wasslurried in methylene chloride (600 mL), cooled to 0° C., and treatedwith triethylamine (24.9 g, 34.3 mL, 246 mmol) andtert-butyldimethylsilyl chloride (24.7 g, 164 mmol). The mixture waswarmed to ambient temperature and stirred overnight, during which itslowly became homogeneous. After dilution with ether (800 mL), themixture was washed with brine (800 mL) and the aqueous layer wasextracted with ether (500 mL). The combined organic layers were dried(sodium sulfate), concentrated, and the residue recrystallized fromhexane to provide 14.2 g (77%) of the title compound as a white powder,mp 118-119° C.: ¹ H-NMR (300 MHz, CDCl₃) d 7.90 (d, J=8.5 Hz, 1H), 7.82(d, J=8.5 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 6.97 (m, 2H), 6.90 (dd, J8.5, 2.0 Hz, 1H), 1.03 (s, 9H), 1.02 (s, 9H), 0.28 (s, 6H), 3.25 (s,6H); IR (CHCl₃) 1733 cm⁻¹ ; MS (FD+) m/e 496 (M+); Anal. calc'd. for C₂₇H₃₆ O₅ Si₂ : C, 65.27; H, 7.32. Found: C, 65.57; H, 7.26. ##STR61## Bythe method described in Preparation 4, the product of Preparation 13(5.0 g, 10.0 mmol) was reacted with a 1.0 M toluene solution ofdiisobutylaluminum hydride (12.0 mL, 12.0 mmol) in toluene (450 mL).Recrystallization from hexane gave 1.26 g of the title compound asmixture with its aldehyde tautomer. Chromatography (silica gel, 2-15%ethyl acetate/hexane) of the mother liquor provided 1.37 g of startingmaterial (approximately 67% pure) and, after recrystallization, 580 mgof title compound for a total output of 1.85 g (37%) of the tautomericmixture: ¹ H NMR (300 MHz) d 10.15 (s, 0.5H), 9.2 (br s, 0.5H), 7.99 (d,J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.50 (m, 0.5H), 7.09 (d, J=2.0Hz, 1H), 6.96 (m, 1H), 6.6-6.7 (m, 2H), 6.55 (m, 0.5H), 1.01 (s, 9H),1.00 (s, 9H), 0.27 (s, 6H), 0.25 (s, 6H); IR (CHCl₃) 3550, 1663 cm⁻¹ ;MS (FD) m/e 499 (MH+); Anal. calc'd. for C₂ 7H₃ 8O₅ Si₂ : C, 65.02; H,7.69. Found: C, 65.32; H, 7.76. ##STR62## By the method described inPreparation 5, the product of Preparation 14 (464 mg, 0.93 mmol) wasreacted with phenol (1.05 g, 11.2 mmol) in chlorobenzene (25 mL)containing anhydrous magnesium sulfate (1.0 g) to yield 467 mg (87%) ofthe crude title compound as an unstable pink foam which was used withoutpurification: ¹ H NMR (300 MHz) d 7.1-7.7 (m, 8H) 6.6-6.9 (m, 3H), 1.01(s, 9H), 1.00 (s, 9H), 0.28 (s, 6H), 0.25 (s, 6H). ##STR63## By themethod described in Preparation 6, the product of Preparation 15 (467mg, 0.81 mmol) was reacted with a 0.5 M THF solution of4-[2-(l-piperidinyl)ethoxy]phenylmagnesium bromide (2.6 mL, 1.62 mmol)in toluene (15 mL). Radial chromatography (silica gel, 2:1 hexane:ethylacetate, 1% methanol under an ammonia atmosphere) provided 500 mg (90%)of the title compound as a colorless, gummy solid: ¹ H NMR (300 MHz) d7.39 (m, 3H), 7.04 (d, J=2.0 Hz, 1H), 6.92 (d, J=8.6 Hz, 2H), 6.78 (d,J=8.4 Hz, 1H), 6.68 (d, J=8.1 Hz, 1H), 6.68 (s, 1H), 6.53 (dd, J=8.2,2.2 Hz, 1H), 6.38 (d, J=2.6 Hz, 1H), 4.05 (t, J=5.9 Hz, 2H), 2.64 (t,J=6.1 Hz, 2H), 2.42 (m, 4H), 1.4-1.6 (m, 4H), 1.3-1.4 (m, 2H), 0.96 (s,9H), 0.95 (s, 9H), 0.20 (s, 6H), 0.19 (s, 6H); ¹³ C NMR (125 MHz) d160.3, 158.0, 156.8, 155.5, 154.0, 148.2, 132.7, 129.8, 121.6, 121.1,119.8, 117.3, 115.3, 113.8, 110.6, 109.8, 109.1, 103.8, 79.0, 66.9,58.5, 55.6, 26.8, 26.0, 26.0, 25.0, 13.7, -4.3, -4.3; MS (FD) m/e 686(M+); Anal. calc'd. for C₄₀ H₅₅ NO₅ Si₂ : C, 70.03; H, 8.08; N, 2.04.Found: C, 70.28; H, 8.14; N, 2.08. EXAMPLE 11 ##STR64## By the proceduredescribed for Example 1, the product of Preparation 16 (520 mg, 0.76mmol) was reacted with 1.0 M TBAF in THF (4.5 mmol) to give, afterradial chromatography (silica gel, 1:1 hexane:ethyl acetate, 10%methanol, under an ammonia atmosphere) 292 mg (72%) of the titlecompound as a bright red foam, which crystallized from carbontetrachloride: ¹ H NMR (300 MHz, dimethylformamide-d₇) d 10.00 (br s,1H), 9.83 (br s, 1H), 7.3-7.5 (m, 3H), 7.10 (s, 1H), 6.98 (d, J=8.5 Hz,2H), 6.7-6.9 (m, 3H), 6.54 (dd, J=8.1, 1.8 Hz, 1H), 6.42 (s, 1H), 4.10(t, J=5.8 Hz, 2H), 2.67 (m, 2H), 2.44 (m, 4H), 1.4-1.6 (m, 4H), 1.3-1.4(m, 2H); ¹³ C NMR (125 MHz, dimethylformamide-d₇) d 160.2, 159.9, 156.8,156.4, 155.1, 147.2, 133.0, 129.5, 121.4, 119.5, 118.9, 115.1, 112.9,109.2, 108.9, 108.3, 104.3, 98.7, 78.5, 66.5, 58.2, 55.3, 26.4, 24.6; IR(KBr) 3220 cm⁻¹ ; HRMS (FAB+) m/e calc'd. for C₂₈ H₂₈ NO₂ 458.1967(MH+), found 458.1974; Anal. calc'd. for C₂₈ H₂₇ NO₄ S.0.25CCl₄ : C,68.40; H, 5.49; N, 2.82. Found: C, 68.58; H, 5.81; N, 2.94. ##STR65## Toa solution of 1-carbomethoxy-6-methoxy-2-tetralone (see, Colvin, Martin,and Shroot, Chemistry and Industry, 2130 (1966)) (18.0 g, 76.3 mmol) andresorcinol (8.9 g, 80.7 mmol) stirring at ambient temperature in toluene(450 mL) was added phosphorus oxychloride (12.0 g, 7.3 mL, 18.3 mmol)dropwise, and the mixture warmed to 80° C. for 12 h. After cooling toroom temperature, the mixture was poured into water (500 mL) andfiltered, rinsing the precipitate with ether. The filtrate layers wereseparated, the aqueous layer was extracted with ethyl acetate (3×500mL), and the combined organic layers were dried (sodium aulfate) andconcentrated. Recrystallization of the residue from methanol provided16.0 g of the title compound as a yellow solid, mp 244-249d° C.: ¹ H NMR(300 MHz, DMSO-d₆) d 10.55 (br s, 1H), 8.24 (d, J=8.6 Hz, 1H), 7.75 (d,J=8.7 Hz, 1H), 6.6-7.0 (m, 4H), 3.76 (s, 3H), 2.8-3.0 (m, 4H); ¹³ C NMR(125 MHz, DMSO-d₆) d 170.3, 160.3, 158.3, 158.1, 153.3, 147.7, 137.5,127.4, 125.8, 122.5, 114.5, 112.6, 112.4, 110.9, 101.4, 54.6, 26.3,22.7; IR (KBr) 3250, 1676, 1618 cm⁻¹ ; MS (FD+) m/e 294 (M+); Anal.calc'd. for C₁₈ H₁₄ O₄ : C, 73.45; H, 4.80. Found: C, 73.15; H, 4.86.##STR66## By the procedure described in Preparation 3, the product ofPreparation 17 (4.17 g, 14.2 mmol) was reacted with ethanethiol (3.53 g,3.95 mL, 56.8 mmol) and aluminum chloride (9.0 g, 67.5 mmol) inmethylene chloride (100 mL). The crude product was further reacted withtriethylamine (8.6 g, 11.9 mL, 85.2 mmol) and tert-butyldimethylsilylchloride (8.6 g, 56.8 mmol) in methylene chloride (100 mL) to provide,after recrystallization from hexane, the title product as a yellowsolid, mp 145-147° C.: ¹ H NMR (300 MHz, CDCl₃) d 8.37 (d, J=8.6 Hz,1H), 7.58 (d, J=9.3 Hz, 1H), 6.83 (s, 1H), 6.81 (m, 2H), 6.72 (d, J=2.4Hz, 1H), 2.8-3.0 (m, 4H), 1.00 (s, 18H), 0.27 (s, 6H), 0.24 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) d 159.8, 158.6, 155.4, 153.9, 147.1, 137.7,128.6, 125.0, 123.9, 119.0, 118.1, 117.5, 117.3, 113.8, 107.5, 27.4,25.7, 25.6, 23.9, 18.3, 18.2, -4.3, -4.4; IR (CHCl₃) 1708, 1612 cm⁻¹ ;MS (FD) m/e 508 (M+). ##STR67## A mixture of 6-methoxytetralone (25 g,142 mmol) and 4-hydroxyaniline (16.3 g, 149 mmol) was heated to 180° C.under a nitrogen stream for 2 h. After cooling to ambient temperature,the solid mass was recrystallized from toluene/methanol: ¹ H NMR (300MHz) d 8.15 (d, J=9.7 Hz, 1H), 6.5-7.9 (m, 6H), 3.80 (s, 3H), 2.84 (t,J=7.3 Hz, 2H), 2.51 (t, J=6.8 Hz, 2H), 1.85 (m, 2H). ##STR68## Theproduct of Preparation 19 (36 g, 134.7 mmol) was dissolved in 1:1methylene chloride:THF (300 mL) and treated with triethylamine (28.6 g,39.4 mL, 283 mmol) and tert-butyldimethylsilyl chloride (30.5 g, 202mmol). The mixture was stirred overnight and additional portions oftriethylamine (6.8 g, 9.4 mL, 67 mmol) and tert-butyldimethylsilylchloride (10.2 g, 67 mmol) were added to drive the reaction tocompletion. After 5 h, the mixture was diluted with ether (500 mL),filtered, concentrated, and the residue washed with hexane/ether. Theextracts were filtered, concentrated, and the residue purified by rapidchromatography (silica gel, 18:1-10:1 hexane:ethylacetate) to give 21.0g (41%) of the title compound as light yellow foam: ¹ H NMR (300 MHz,CDCl₃) d 8.32 (d, J=9.7 Hz, 1H), 6.86 (m, 3H), 6.73 (m, 3H), 3.92 (t,J=5.8 Hz, 2H), 2.57 (t, J=6.8 Hz, 2H), 1.96 (m, 2H), 1.05 (s, 9H), 0.26(s, 6H). ##STR69## The product of Preparation 20 (10.2 g, 26.8 mmol) wasdissolved in methylene chloride (100 mL), cooled to 0° C., and treatedwith triethylamine (3.8 g, 5.2 mL, 37.5 mmol) followed by a solution of2,5-dimethoxybenzoylchloride (6.72 g, 33.5 mmol) in dichloromethane (25mL). The mixture was warmed to reflux overnight, then treated withadditional triethylamine (1.4 g, 1.9 mL, 13.4 mmol) and acid chloride(2.7 g, 13.4 mmol) and heating continued for an additional 12 h. Afterconcentration in vacuo, the residue was dissolved in ether (250 mL),washed with brine (250 mL), dried (sodium sulfate), and concentrated.Purification of the residue by chromatography (silica gel, 9:1-4:1hexane:ethyl acetate) provided 10.3 g of the title compound as a whitefoam: ¹ H NMR (300 MHz, CDCl₃) d 6.4-7.6 (br m, 11H), 5.83 (br S, 1H),3.4-3.8 (br m, 9H), 1.9-3.0 (br m, 4H), 0.95 (2 br s, 9H), 0.14 (2 br s,6H); IR (CHCl₃) 1651, 1607, 1507 cm⁻¹ ; MS (FD) m/e 545 (M+); Anal.calc'd for C₃₂ H₃₉ NO₅ Si: C, 70.43; H, 7.20; N, 2.57. Found: C, 70.53;H, 7.26; N, 2.76. ##STR70## A solution of the product of Preparation 21(2.73 g, 5 mmol) in benzene (250 mL) was degassed via 3 freeze/pump/thawcycles and irradiated with a 450 Watt internal mercury lamp in a quartzimmersion well under nitrogen. After 22 h, the mixture was concentratedand the residue purified by chromatography (silica gel, 20:1toluene:ether) to provide 675 mg (26%) of the title compound as a yellowfoam. An analytical sample was obtained by crystallization fromhexane/ether as light yellow crystals, mp 194-95° C.: ¹ H NMR (300 MHz,CDCl₃) 7.94 (d, 2.8 Hz, 1H), 7.73 (d, 8.9 Hz, 1H), 7.32 (dd, J 8.9, 2.8Hz, 1H), 7.17 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 6.76 (d, J=2.6Hz, 1H), 6.67, (d, J=8.8 Hz, 1H), 6.35 (dd, J=8.8, 2.7 Hz, 1H), 3.94 (s,3H), 3.75 (s, 3H), 3.90 (s, 4H), 0.99 (s, 9H), 0.21 (s, 6H); ¹³ C NMR(125 MHz, CDCl₃) d 162.6, 158.3, 157.7, 154.4, 139.7, 134.3, 133.6,129.9, 129.8, 128.1, 126.2, 123.7, 123.2, 122.6, 119.8, 114.9, 112.7,110.4, 108.6, 55.3, 54.8, 29.3, 25.5, 23.5, 18.1, -4.4; IR (CHCl₃) 1640,1615, 1507 cm⁻¹ ; MS (FD+) m/e 513 (M+); Anal. calc'd for C₃ ₁ H₃₅ NO₄Si: C, 72.48; H, 6.87; N, 2.73. Found: C, 72.66, H, 6.95; N, 2.86.##STR71## The product of Preparation 22 (790 mg, 1.5 mmol) was dissolvedin 3:2 acetonitrile:methylene chloride (50 mL) and treated with hydrogenfluoride-pyridine (10 mL) in 2 portions at 1 h intervals. After furtherstirring for 1 h, the mixture was diluted with THF (100 ml) andfiltered, washing with methanol and ether. The filtrates were dilutedwith THF (200 mL) and washed with brine (200 mL) and saturated sodiumbicarbonate (200 mL). The combined aqueous layers were extracted withTHF (100 mL) and the combined organic layers were dried (sodium sulfate)and concentrated to provide 340 mg (57%) of a yellow powder, mp250-275d° C., which was used without purification: ¹ H NMR (300 MHz,dimethylformamide-d₇) d 9.80 (br s, 1H), 7.91 (d, J=9.7 Hz, 1H), 7.81(d, J=1.9 Hz, 1H), 7.44 (dd, J=9.7, 1.9 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H),6.8-7.0 (m, 4H), 6.47 (dd, J=8.7, 1.9 Hz, 1H), 3.94 (s, 3H), 3.74 (s,3H), 2.89 (m, 4H); MS (FD+) m/e 399 (M+). EXAMPLE 12 ##STR72## To asolution of the product of Preparation 23 (340 mg, 0.85 mmol),triphenylphosphine (446 mg, 1.7 mmol), and 1-(2-hydroxyethyl)piperidine(275 mg, 282 mL, 2.1 mmol) in THF (20 mL) was added diethylazodicarboxylate (DEAD) (296 mg, 268 mL, 1.7 mmol) and the mixture wasstirred at ambient temperature overnight. After concentation in vacuo,chromatography (silica gel, 1:1 hexane:ethyl acetate, 5-20% methanol,0.1% ammonium hydroxide) provided 338 mg (66%) of the title compound asa yellow foam: ¹ H NMR (300 MHz) d 7.82 (m, 2H), 7.35 (dd, J=9.7, 2.9Hz, 1H), 7.23 (d, J=9.7 Hz, 2H), 6.91 (d, J=9.7 Hz, 2H), 6.82 (m, 1H),6.70 (d, J=9.7 Hz, 1H), 6.38 (dd, J=9.7, 1.9 Hz, 1H), 4.12 (t, J=5.8 Hz,2H), 3.90 (s, 3H), 3.70 (s, 3H), 2.86 (m, 6H), 2.65 (m, 4H), 1.5-1.7 (m,4H), 1.4-1.5 (m, 2H). EXAMPLE 13 ##STR73## A solution of the product ofExample 13 (195 mg, 0.39 mmol) in methylene chloride (25 mL) was treatedwith ethanethiol (200 mg, 220 mL, 3.2 mmol) and aluminum chloride (320mg, 2.4 mmol). After stirring for 4 h at ambient temperature, themixture was quenched carefully with THF (25 mL) and saturated sodiumbicarbonate (25 mL). The layers were separated, the aqueous layer wasextracted with THF (25 mL), and the combined organic layers were dried(sodium sulfate) and concentrated. The residue was purified by radialchromatography (silica gel, 1:1 hexane:ethyl acetate, 10-20% methanol,under an ammonia atmosphere) to provide 110 mg (60%) of the titlecompound as a tan foam. An analytical sample was crystallized frommethanol as a light red solid: ¹ H NMR (300 MHz, dimethylformamide-d₇) d9.92 (br s, 1H), 9.74 (br s, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.5Hz, 1H), 7.69 (d, J 9.0 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.23 (d, J=2.0Hz, 1H), 6.98 (dd, J=9.0, 2.1 Hz, 1H), 6.84 (dd, J=8.4, 2.1 Hz, 1H),6.73 (m, 5H), 3.92 (t, J=5.9 Hz, 2H), 2.57 (t, J=5.9 Hz, 2H), 2.38 (m,4H), 1.4-1.5 (m, 4H), 1.3-1.4 (m, 2H); IR (KBr) 3560, 3490 cm⁻¹ ; MS(FD+) m/e 466 (M+); Anal. calc'd. for C₃₀₀ H₃₀ N₂ O₃.0.5H₂ O: C, 75.75;H, 6.58; N, 5.89. Found: C, 75.82; H, 6.76; N, 5.95. EXAMPLE 152,8-dihydroxy-5-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-5H-benzo[b]naphtho[2,1-d)pyran

This compound is prepared in accordance with the foregoing teaching andexamples. ##STR74##

EXAMPLE 10a ##STR75## By the procedure described for Example 1, theproduct of Preparation 11 (458 mg, 0.66 mmol) was reacted with 1.0 MTBAF in THF (3.3 mmol) to give, after radial chromatography (silica gel,1:1 hexane:ethyl acetate, 10-20% methanol, under an ammonia atmosphere)and crystallization from acetone/ether 296 mg (72%) of the titlecompound as a red solid, mp 118-123d° C.: ¹ H NMR (300 MHz) δ 7.35 (d,J=2.1 Hz, 1H), 7.26 (d, J=8.6 Hz, 2H), 7.16 (d, J=8.1 Hz, 1H), 7.13 (d,J=8.5 Hz, 1H), 6.81 (m, 3H), 6.62 (s, 1H), 6.45 (dd, J=8.3, 2.3 Hz, 1H),6.35 (d, J=2.2 Hz, 1H), 3.98 (t, J=6.2 Hz, 2H), 2.78 (t, J=6.2 Hz, 2H),2.56 (q, J=7.1 Hz, 4H), 0.97 (t, J=7.1 Hz, 6H); ¹³ C NMR (75 MHz) δ160.2, 159.7, 155.9, 153.5, 141.1, 132.9, 131.5, 130.2, 129.9, 125.4,124.8, 122.7, 115.2, 112.8, 109.6, 108.9, 104.8, 78.1, 67.5, 52.6, 48.3,12.4; IR (KBr) 3311 cm⁻¹ ; MS (FD+) m/e 462 (MH+); Anal. calc'd. for C₂₇H₂₇ NO₄ S: C, 70.04; H, 6.13; N, 3.04. Found: C, 70.26; H, 5.90; N,3.03. EXAMPLE 10b ##STR76## By the procedure described for Example 1,the product of Preparation 12 (521 mg, 0.74 mmol) was reacted with 1.0 MTBAF in THF (3.7 mmol) to give, after radial chromatography (silica gel,1:1 hexane:ethyl acetate, 15% methanol, under an ammonia atmosphere) andcrystallization from acetone/ether 286 mg (81%) of the title compound asa red solid, mp 147-153d° C.: ¹ H NMR (300 MHz) δ 7.35 (d, J=2.1 Hz,1H), 7.25 (d, J=8.6 Hz, 2H), 7.16 (d, J=8.3 Hz, 1H), 7.14 (d, J=8.6 Hz,1H), 6.81 (m, 3H), 6.62 (s, 1H), 6.46 (dd, J=8.2, 2.2 Hz, 1H), 6.35 (d,J=2.2 Hz, 1H), 4.04 (t, J=5.7 Hz, 2H), 3.56 (t, J=4.7 Hz, 4H), 2.68 (t,J=5.7 Hz, 2H), 2.47 (t, J=4.3 Hz, 4H); ¹³ C NMR (75 MHz) δ 160.0, 159.7,155.9, 153.5, 141.1, 132.9, 131.4, 129.8, 129.7, 125.4, 124.8, 122.6,115.2, 112.8, 109.6, 108.9, 104.7, 78.0, 67.2, 66.5, 58.1, 54.7; IR(KBr) 3471 cm⁻¹ ; MS (FD+) m/e 475 (MH+); Anal. calc'd. for C₂₇ H₂₅ NO₅S.0.25H₂ O: C, 67.54; H, 5.36; N, 2.92. Found: C, 67.58; H, 5.51; N,2.57. ##STR77## A mixture of the product of Preparation 12a (14.0 g, 49mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (11.6 g, 51mmol) in dichloroethane (350 mL) was heated briefly to reflux, inducingthe formation of a precipitate. The mixture was filtered hot, rinsingthe precipitate with methylene chloride, and the mother liquorconcentrated in vacuo. The crude product was then rinsed several timeswith acetone and dried in vacuo to provide 12.6 g (91%) of the titleproduct as a white fluffy solid: ¹ H NMR (300 MHz, CDCl₃) 68.55 (d,J=8.9 Hz, 1H), 7.70 (dd, J=1.2, 8.0 Hz, 1H), 7.4-7.6 (m, 2H), 7.33 (m,2H), 7.13 (dd, J=2.3, 8.9 Hz, 1H), 3.91 (s, 3H); IR (CHCl₃) 1722 cm⁻¹ ;MS (FD) m/e 282 (M+); Anal. calc'd for C₁₆ H₁₀ O₃ S: C, 68.07; H, 3.57.Found: C, 67.80; H, 3.53. ##STR78## To a mechanically stirred slurrry ofthe product of Preparation 12b (9.0 g, .2 mmol) in methylene chloride(235 mL) was added ethanethiol (5.9 mL, 80 mmol) followed by aluminumchloride 15.8 g, 120 mmol), portionwise. The reaction mexture wasstirred at ambient temperature for 1 h, then cooled to 0° C. andquenched cautiously with tetrahydrofuran (THF) followed by saturatedsodium bicarbonate. The mixture was diluted with THF, the layersseparated, and the aqueous layer was washed several times with THF. Thecombined organic layers were dried (sodium sulfate) and concentrated toyield 7.4 g (86%) of crude phenol as an off-white, slightly pink solid,which was used without further purification.

The crude product was slurried in methylene chloride (200 mL) andtreated with triethylamine (19.1 mL, 140 mmol) andtert-butyldimethylsilyl chloride (10.4 g, 69 mmol). The mixture wasstirred at ambient temperature overnight, during which it becamehomogeneous. After dilution with hexane, the mixture was washed twotimes with brine. The organic layer was dried (sodium sulfate),concentrated, and the residue recrystallized from hexane to provide 9.8g (80%) of the title compound as a fluffy white solid: ¹ H NMR (300 MHz,CDCl₃) 68.55 (d, J=8.5 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.4-7.6 (m, 2H),7.34 (m, 2H), 7.08 (dd, J=2.2, 8.8 Hz, 1H), 1.02 (s, 9H), 0.26 (s, 6H);IR (CHCl₃) 1717 cm ¹ ; MS (FD) m/e 382 (M+); Anal. calc'd for C₂₁ H₂₂ O₃SSi: C, 65.93; H, 5.80. Found: C, 66.23; H, 5.84. ##STR79## A solutionof the product from Preparation 12c (3.5 g, 9.1 mmol) in toluene (490mL) was cooled to -78° C. and treated dropwise with a 1.0 M toluenesolution of diisobutylaluminum hydride (11.0 mL, 11 mmol) at a ratemaintaining the internal temperature below -70° C. The mixture wasstirred for approximately 4 h, then quenched with methanol (14 mL), 10%aqueous citric acid (140 mL), and water (315 mL). The aqueous layer wasextracted three times with methylene chloride (560 mL). The organiclayers were dried (sodium sulfate), concentrated, and the remnantchromatographed (silica gel, gradient of 2% ethyl acetate in hexane to20% ethyl acetate in hexane) to yield 1.7 g (49%) of the title compoundas a white crystalline solid: ¹ H NMR (300 MHz) δ 7.77 (d, J=8.6 Hz,1H), 7.50 (d, J=2.1 Hz, 1H), 7.42 (m, 1H), 7.28 (m, 1H), 7.05 (m, 2H),6.89 (m, 1H), 6.46 (m, 1H) 1.02 (s, 9H), 0.26 (s, 6H); IR (CHCl₃) 2959,2932, 2861, 1612, 1598 cm⁻¹ ; MS (FD) m/e 384 (M+); Anal. calc'd for C₂₁H₂₄ O₃ SSi: C, 65.59; H, 6.29. Found: C, 65.51; H, 6.32. ##STR80## Theproduct of Preparation 12d (1.5 g, 3.9 mmol) and phenol (2.7 g, 29 mmol)were dissolved in chlorobenzene (50 mL) and the mixture was stirred for3.5 h at reflux. The mixture was concentrated and residue redissolved inchlorobenzene and reconcentrated in vacuo at approximately 70° C. Theresidue was then dissolved in diethyl ether, washed three times withsaturated sodium carbonate, water and brine. The organic layer was dried(sodium sulfate) and concentrated to yield 1.7 g (93%) of the titlecompound as a fluffy white solid which was used without furtherpurification: the ¹ H NMR spectrum (300 MHz) was consistent with thestructure.

EXAMPLE 10c ##STR81## To a solution of the product of Preparation 12e(1.7 g, 3.6 mmol) in toluene (50 mL) at 00C was added a 0.2 M THFsolution of 4-[2-(1-piperidinyl)ethoxy]phenylmagnesium bromide (preparedfrom the corresponding bromobenzene and magnesium turnings, catalyzed byiodine in THF, 45.3 mL, 9.1 mmol). The mixture was allowed to warm toroom temperature and stirred for 14 h. After quenching with water, themixture was extracted three times with methylene chloride, and theorganic layer was dried (sodium sulfate) and concentrated. The remnantwas purified via chromatography (silica gel, hexane-4:1 hexane:ethylacetate) to give 2.6 g (126%) of the partially purified silylatedproduct.

To a solution of the partially purified product (2.6 g, 3.6 mmol) in THF(40 mL), was added a 1.0 M THF solution of tetra-n-butylammoniumfluoride (TBAF) (5.0 mL, 5.0 mmol). The solution was stirred at ambienttemperature for 10 min, then diluted with ethyl acetate and washed fivetimes with saturated sodium bicarbonate and brine. The organic layerswere dried (sodium sulfate) and concentrated. The remnant was purifiedvia chromatography (silica gel, 1:1 hexane:ethyl acetate, 0-10%methanol, 0.1% ammonium hydroxide) to give 0.93 g (56%) of the titlecompound as white fluffy solid: ¹ H NMR (300 MHz) 56.7-7.4 (m, 12H),4.02 (t, J=6.0 Hz, 2H), 2.63 (t, J=6.0 Hz, 1H), 2.41 (m, 4H), 1.49 (m,4H), 1.37 (m, 2H); IR (KBr) 2934, 1609 cm⁻¹ ; MS (FD) m/e 457 (M+); HRMS(FAB) m/e calc'd for C₂₈ H₂₈ NO₃ S (MH+): 458.1790. Found: 458.1798;Anal. calc'd for C₂₈ H₂₇ NO₃ S.0.5H₂ O: C, 72.08; H, 6.05; N, 3.00.Found: C, 71.97; H, 6.04; N, 3.06. ##STR82## To a mechanically stirredslurrry of 3-Methoxy-6--H-[1]benzothieno[3,2-c][1]benzopyran-6-one(Journal of Organic Chemistry, 40:3169 (1975))(1.0 g, 3.6 mmol) inmethylene chloride (30 mL) was added ethanethiol (1.4 mL, 18.0 mmol)followed by aluminum chloride (1.6 g, 12 mmol), portionwise. Thereaction mixture was stirred at ambient temperature for 1.5 h, thencooled to 0° C. and quenched cautiously with tetrahydrofuran (THF)followed by saturated sodium bicarbonate. The mixture was diluted withTHF, the layers separated, and the aqueous layer was washed severaltimes with THF. The combined organic layers were dried (sodium sulfate)and concentrated to yield the crude phenol, which was used withoutfurther purification. The crude product was slurried in methylenechloride (30 mL) and treated with triethylamine (2.5 mL, 18 mmol) andtert-butyldimethylsilyl chloride (1.3 g, 9.0 mmol). The mixture wasstirred at ambient temperature overnight, during which it becamehomogeneous. After dilution with hexane, the mixture was washed twotimes with brine. The organic layer was dried (sodium sulfate),concentrated, and the residue purified by chromatography (silica gel,hexane-4:1 hexane:ethyl acetate) to provide 0.95 g (69%) of the titlecompound as a fluffy white solid: ¹ H NMR (300 MHz, acetone-d₆) δ 8.57(d, J=7.8 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H),7.5-7.7 (m, 2H), 6.99 (m, 2H), 1.03 (s, 9H), 0.33 (s, 6H); IR (CHCl₃)1716 cm⁻¹ ; MS (FD) m/e 382 (M⁺); Anal. cacl'd for C₂₁ H₂₂ O₃ SSi: C,65.93; H, 5.80. Found: C, 66.11; H, 5.83. ##STR83## A solution of theproduct from Preparation 12f (5.0 g, 13 mmol) in toluene (700 ML) wascooled to -78° C. and treated dropwise with a 1.0 M toluene solution ofdiisobutylaluminum hydride (15.7 mL, 15.7 mmol) at a rate maintainingthe internal temperature below -70° C. The mixture was stirred forapproximately 4 h, then quenched with methanol (20 mL), 10% aqueouscitric acid (200 mL), and water (450 mL). The aqueous layer wasextracted three times with methylene chloride (800 mL). The organiclayers were dried (sodium sulfate), concentrated, and the remnantchromatographed (silica gel, gradient of 2% ethyl acetate in hexane to20% ethyl acetate in hexane) to yield 1.7 g (45%) of the title compoundas a white fluffy solid: ¹ H NMR (300 MHz) δ 7.96 (d, J=7.7 Hz, 1H),7.83 (d, J=6.7 Hz, 1H), 7.3-7.8 (m, 3H), 6.91 (m, 1H), 6.62 (m, 2H),1.00 (s, 9H), 0.26 (s, 6H); IR (CHCl₃) 2958, 2932, 2861, 1616, 1594 cm⁻¹; MS (FD) m/e 384 (M⁺); Anal. calc'd for C₂₁ H₂₄ O₃ SSi: C, 65.59; H,6.29. Found: C, 65.31; H, 6.18. ##STR84## The product of Preparation 12g(0.09 g, 0.24 mmol) and phenol (0.25 g, 2.6 mmol) were dissolved inchlorobenzene (10 mL) and the mixture was stirred for 3 h at 100° C. Themixture was concentrated and residue redissolved in chlorobenzene andreconcentrated in vacuo at approximately 70° C. The residue was thendissolved in diethyl ether, washed five times with saturated sodiumcarbonate, water and brine. The organic layer was dried (sodium sulfate)and concentrated to yield 0.11 g (100%) of the title compound as afluffy white solid which was used without further purification: the ¹ HNMR spectrum (300 MHz) was consistent with the structure.

EXAMPLE 10d ##STR85## To a solution of the product of Preparation 12 h(0.28 g, 0.61 mmol) in toluene (20 mL) at 0° C. was added a 0.2 M THFsolution of 4-[2-(1-piperidinyl)ethoxy]phenylmagnesium bromide (preparedfrom the corresponding bromobenzene and magnesium turnings, catalyzed byiodine in THF, 7.6 mL, 1.5 mmol). The mixture was allowed to warm toroom temperature and stirred for 1 h. After quenching with water, themixture was extracted six times with methylene chloride, and the organiclayer was dried (sodium sulfate) and concentrated. The remnant waspurified via chromatography (silica gel, 4:1-1:1 hexane:ethyl acetate)to give 0.41 g (119%) of the partially purified silylated product.

To a solution of the partially purified product (0.41 g, 0.72 mmol) inTHF (10 mL), was added a 1.0 M THF solution of tetra-n-butylammoniumfluoride (TBAF) (0.67 mL, 0.67 mmol). The solution was stirred atambient temperature for 10 min, then diluted with ethyl acetate andwashed three times with saturated sodium bicarbonate and brine. Theorganic layers were dried (sodium sulfate) and concentrated. The remnantwas triturated from methylene chloride, and the precipitate filtered andrinsed methylene chloride to give 0.23 g (82%) of the title compound aswhite powdery solid. The solid was slurried in methanol andtrifluoroacetic acid was added dropwise until all the material went intosolution, the insoluble material was filtered away, and the motherliquor was concentrated in vacuo to yield 0.28 g (80%) of the TFA saltas a fluffy orange solid: ¹ H NMR (300 MHz) 67.95 (m, 1H), 7.38 (m, 1H),7.2-7.3 (m, 5H), 6.90 (d, J=8.6 Hz, 2H), 6.76 (s, 1H), 6.51 (dd, J=2.2,8.2 Hz, 1H), 6.38 (d, J=2.3 Hz, 1H), 4.44 (t, J=4.9 Hz, 2H), 3.5-3.7 (m,4H), 3.0-3.2 (m, 2H), 1.7-2.0 (m, 5H), 1.4-1.7 (m, 1H); IR (CHCl₃) 3271,3022, 3009, 1670, 1610 cm⁻¹ ; MS (FD) m/e 457 (M⁺); HRMS (FAB) m/ecalc'd for C₂₈ H₂₈ NO₃ S (MH⁺): 458.1790. Found: 458.1781; Anal. calc'dfor C₂₈ H₂ NO₃ S.CF₃ COOH.1.2H₂ O: C, 60.69; H, 5.12; N, 2.36. Found: C,60.62; H, 4.82; N, 2.40. ##STR86## A mixture of the product ofPreparation 10 (7.0 g, 13.8 mmol) and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (3.3 g, 14.5 mmol) indichloroethane (100 mL) was heated at reflux overnight, inducing theformation of a precipitate. The mixture was filtered hot, rinsing theprecipitate with methylene chloride, and the mother liquor concentratedin vacuo. The remnant was partitioned between hexane:ether and water,and the organic layer was dried (magnesium sulfate), cocentrated, andrecrystallized from hexane to provide 5.5 g (79%) of the title productas a tan solid, mp 154-156° C.: ¹ H-NMR (300 MHz, CDCl₃) δ 9.69 (d,J=9.4 Hz), 8.80 (s, 2H), 8.01 (d, J=9.5 Hz), 7.34 (dd, J=9.3,2.5 Hz,1H), 7.28 (d, J=5.4 Hz, 1H), 6.90 (m, 2H), 1.05 (s, 9H), 1.03 (s, 9H),0.29 (s, 12H); IR (CHCL₃) 1711, 1622, 1604 cm⁻¹ ; MS (FD) m/e 506 (M+);Anal. calc'd. for C₂₉ H₃₈ O₄ Si₂ : C, 68.72; H, 7.57. Found: C, 68.93;H, 7.36. ##STR87## By the procedure described for Preparation 4, theproduct of Preparation 18a (5.0 g, 9.9 mmol) was reacted with 1.0 Mdiisobutylaluminum hydride in toluene (11.9 mL, 11.9 mmol) to give,after recrystallization from hexane:ether, 4.14 g (82%) of the titlecompound as a white solid, mp 188-190° C.: ¹ H NMR (300 MHz, CDCl₃) δ7.98 (d, J=9.1 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H),7.75 (d, J=8.2 Hz, 1H), 7.23 (d, J=2.3 Hz, 1H), 7.18 (dd, J=9.0, 2.4 Hz,1H), 7.06 (d, J=7.4 Hz, 1H), 6.67 (m 2H), 3.24 (d, J=7.7 Hz, 1H), 1.04(s, 9H), 1.02 (s, 9H), 0.27 (s, 6H), 0.27 (s, 6H) IR (CHCl₃) 3574 cm⁻¹ ;MS (FD) m/e 508 (M+); Anal. calc'd. for C₂₉ H₄₀ O₄ Si₂ : C, 68.44; H,7.94. Found: C, 68.63; H, 8.11. ##STR88## By the procedure described forPreparation 5, the product of Preparation 18b (3.5 g, 6.88 mmol) wasreacted with phenol (3.2 g, 34.3 mmol) to give 3.82 g (95%) of the titlecompound as an amorphous white solid which was used without furtherpurification: ¹ H NMR (300 MHz) δ 7.9-8.1 (m, 4H), 7.61 (s, 1H), 7.3-7.5(m, 3H), 7.2-7.3 (m, 3H), 7.11 (t, J=7.3 Hz, 1H), 6.74 (dd, J=8.5, 2.3Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 1.03 (s, 9H), 0.99 (s, 9H), 0.29 (s,6H), 0.24 (s, 6H); ¹³ C NMR (75 MHz) δ 157.9, 157.6, 154.3, 151.8,135.1, 130.4, 130.1, 126.4, 125.8, 125.1, 124.9, 123.9, 123.6, 123.1,121.1, 118.5, 116.7, 116.2, 115.7, 110.0, 94.8, 26.0, 25.9, 18.8, 18.7,-4.3, -4.4; MS (FD) m/e 584 (M+). ##STR89## By the procedure describedfor Preparation 6, the product of Preparation 18c (3.5 g, 6.0 mmol) wasreacted with a 0.2 M THF solution of4-[2-(1-piperidinyl)ethoxy]phenylmagnesium bromide to provide, afterchromatography (silica gel, 3:2 hexane:ethyl acetate, 0.1% ammoniumhydroxide), 3.5 g (84%) of the title compound as a colorless gummysolid: ¹ H NMR (300 MHz) δ 7.97 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.7 Hz,1H), 7.76 (d, J=8.3 Hz, 2H), 7.35 (d, J=2.4 Hz, 1H), 7.10 (m, 3H), 7.02(s, 1H), 6.73 (d, J=8.7 Hz, 2H), 6.53 (dd, J=8.3, 2.4 Hz, 1H) 6.37 (d,J=2.2 Hz, 1H), 3.95 (t, J=6.0 Hz, 2H), 2.538 t, J=6.0 Hz, 2H), 2.38 (m,4H), 1.4-1.5 (m, 4H), 1.3-1.4 (m, 2H), 1.00 (s, 9H), 0.94 (s, 9H), 0.25(s, 6H), 0.19 (s, 6H); ¹³ C NMR (75 MHz) δ 159.8, 157.6, 154.1, 154.0,135.0, 132.2, 130.1, 128.6, 127.3, 126.3, 126.2, 125.6, 124.7, 123.4,121.6, 118.0, 116.5, 115.0, 114.5, 110.3, 76.0, 66.8, 53.5, 55.6, 26.8,26.0, 26.0, 25.0, 18.7, 18.7, -4.2, -4.3; MS (FD) m/e 696 (M+); Anal.calc'd. for C₄₂ H₅₇ NO₄ Si₂ : C, 72.46; H, 8.27; N, 2.01. Found: C,72.53; H, 8.49; N, 2.08.

EXAMPLE 11b ##STR90## By the procedure described for Example 1, theproduct of Preparation 18d (3.4 g, 4.9 mmol) was reacted with a 1.0 MTBAF in THF (24.4 mmol) to provide, after chromatography (silica gel,1:1 hexane:ethyl acetate, 10% methanol, 0.1% ammonium hydroxide) andtrituration with ether, 2.2 g (96%) of the title compound as a whitesolid, mp 158-161° C.: ¹ H NMR (300 MHz) δ 7.89 (d, J=8.7 Hz, 1H), 7.77(d, J=8.7 Hz, 1H), 7.68 (m, 2H), 7.23 (d, J=2.4 Hz, 1H), 7.09 (m, 3H),6.97 (s, 1H), 6.71 (d, J=8.7 Hz, 2H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 6.36(d, J=2.3 Hz, 1H), 3.95 (t, J=6.0 Hz, 2H), 2.60 (t, J 6.0 Hz, 2H), 2.40(m, 4H), 1.4-1.5 (m, 4H) 1.3-1.4 (m, 2H); ¹³ C NMR (75 MHz) 6159.5,159.5, 155.8, 153.9, 135.0, 132.4, 130.1, 128.0, 126.7, 125.6, 125.4,125.3, 124.7, 121.4, 119.9, 116.1, 114.8, 111.0, 110.1, 105.5, 75.8,66.1, 58.3, 55.3, 26.3, 24.7; IR (KBr) 2934 cm⁻¹ ; MS (FD) m/e 468(MH+); Anal. calc'd. for C₃₀ H₂₉ NO₄.H₂ O: C, 74.19; H, 6.45; N, 2.88.Found: C, 74.13; H, 6.45; N, 2.88. ##STR91## A mixture of the product ofPreparation 22 (100 mg, 0.19 mmol) and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (47 mg, 0.21 mmol) indichloroethane (10 mL) was heated at reflux for 2 h, inducing theformation of a precipitate. The mixture was cooled to room temperature,filtered, and the filtrate diluted with CH₂ Cl₂ (70 mL), washed with 1 Nsodium hydroxide (2×70 mL), dried (Na₂ SO₄) and concentrated to provide98 mg (98%) of the title compound as a white, crystalline solid, np211-213° C.: ¹ H NMR (300 MHz, CDCl₃) δ 8.21 (d, J=9.0 Hz, 1H), 8.16 (d,J=8.9 Hz, 1H), 7.95 (d, J=2.8 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.37 (dd,J=9.0, 2.8 Hz, 1H), 7.25 (d, J=9.7 Hz, 1H), 7.21 (d, J=8.7 Hz, 2H), 7.08(d, J=2.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 6.66 (dd, J=9.7, 2.8 Hz, 1H),3.94 (s, 3H), 3.87 (s, 3H), 1.02 (s, 9H), 0.25 (s, 6H); ¹³ C NMR (75MHz, CDCl₃) δ 163.1, 159.2, 156.9, 154.9, 137.3, 136.3, 133.8, 129.8,128.3, 127.4, 126.4, 123.9, 123.7, 122.9, 120.7, 120.5, 119.5, 116.5,115.7, 109.1, 106.9, 55.5, 55.1, 25.7, 18.3, -4.2; IR (CHCl₃) 1646, 1619cm⁻¹ ; MS (FD) m/e 511 (M+); Anal. calc'd. for C₃₁ H₃₃ NO₄ Si: C, 72.75;H, 6.51; N, 2.74. Found: C, 72.57; H, 6.50; N, 2.83. ##STR92## Theproduct of Preparation 22a (6.8 g, 13.3 mmol) was dissolved in 1:1acetonitrile:methylene chloride (200 mL) and treated with hydrogenfluoride-pyridine (80 mL) for 1 h. The mixture was diluted with brine(500 mL) and extracted with THF (3×300 mL). The combined organic layerswere neutralized with saturated sodium bicarbonate and the resultingaqueous layer was washed with THF (2×500 mL). All aqueous layers werethen combined and washed with THF (500 mL), and the combined organiclayers were dried (sodium sulfate), and concentrated, and the solidresidue was washed with acetone to provide 5.27 g (100%) of the titlecompound as an off-white powder, mp 310d° C.: ¹ H NMR (300 MHz, DMSO-d₆)δ 9.79 (bs, 1H), 3.52 (d, J=9.0 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H), 7.72(m, 2H), 7.47 (dd, J=8.7, 2.3 Hz, 1H), 7.31 (d, 2.1 Hz, 1H), 7.21 (d,J=9.6 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.3 Hz, 2H), 6.68 (dd,J=9.3, 2.6 Hz, 1H), 3.87 (s, 3H), 3.79 (s, 3H); MS (FD) m/e 397 (M+).EXAMPLE 12a ##STR93## By the procedure described for Example 14, theproduct of Example 12 (310 mg, 0.61 mmol) was reacted with ethanethiol(189 mg, 3.1 mmol) and aluminum chloride (611 mg, 4.6 mmol) to provideafter radial chromatography (silica gel, 1:1 hexane:ethyl acetate,10-20% methanol, under an ammonia atmosphere) 237 mg (81%) of the titlecompound as a yellow foam which crystallized upon trituration withether, mp 166-174d° C.: ¹ H NMR (300 MHz, methanol-d₄) δ 7.80 (d, J=8.9Hz, 1H), 7.73 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.9, 2.7 Hz, 1H), 7.19 (d,J=3.8 Hz, 2H), 6.97 (d, J=8.9 Hz, 2H), 6.66 (d, J=2.5 Hz, 1H), 6.56 (d,J=8.7 Hz, 1H), 6.21 (dd, J=8.7, 2.6 Hz, 1H), 4.16 (t, J=5.6 Hz, 2H),2.86 (s, 4H), 2.81 (t, J=5.6 Hz, 2H), 2.59 (m, 4H), 1.6-1.7 (m, 4H),1.4-1.6 (m, 2H); IR (CHCl₃) 3673, 1637, 1602 cm⁻¹ ; MS (FD) m/e 482(M+); Anal. calc'd. for C₃₀ H₃₀ N₂ O₄.H₂ O: C, 71.96; H, 6.46; N, 5.60.Found: C, 71.68; H, 6.63; N, 5.46. EXAMPLE 12b ##STR94## A solution ofthe Product of Example 12 (350 mg, 0.69 mmol) in THF (25 mL) was treatedwith lithium aluminum hydride (129 mg, 3.4 mmol) inducing a moderateexotherm. The mixture was allowed to return co room temperature andstirred for 2 h, then briefly warmed to reflux, cooled, and quenchedwith ethyl acetate (50 mL) followed by saturated ammonium chloride (50mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), andthe combined organic layers were dried (sodium sulfate), concentrated,and purified via radial chromatography (silica gel, 1:1 hexane:ethylacetate, 5% methanol, under an ammonia atmosphere) to provide 248 mg(64%) of the title compound as a yellow foam: ¹ H NMR (300 MHz, CDCl₃) δ7.2° d, J=8.5 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.79 (m, ¹ H), 6.72 (d,J=2.6 Hz, 1H), 6.65 (d, 9.0 Hz, 2H), 6.58 (d, J=2.6 Hz, 1H), 6.52 (dd,J=8.6, 2.6 Hz, 1H), 4.65 (s, 2H), 3.94 (t, J=6.1 Hz, 2H), 3.74 (s, 3H),3.74 (s, 3H), 2.96 (dd, J=8.3, 5.6, 2H), 2.81 (dd, J=8.3, 5.9 Hz, 2H),2.66 t, J 6.1 Hz, 2H), 2.43 (m, 4H), 1.5-1.6 (m, 4H), 1.3-1.5 an, 2H) ¹³C NMR (75 MHz, CDCl₃) δ 158.5, 158.3, 153.3, 141.7, 138.4, 134.6, 132.3,126.6, 126.2, 125.3, 122.9, 121.7, 120.5, 114.9, 113.4, 112.3, 111.2,111.0, 65.8, 57.2, 55.6, 55.2, 55.1, 54.8, 29.0, 25.7, 24.0, 22.2; IR(CHCl₃) 2610, 1506 cm⁻¹ ; MS (FD) m/e 496 (M+); Anal. calc'd. for C₃₂ H₃61N₂ O₃ : C, 77.37; H, 7.32; N, 5.64. Found: C, 77.25; H, 7.12; N, 5.75.EXAMPLE 12c ##STR95## By the method described for Example 12, theproduct of Preparation 23a (4.8 g, 12.1 mmol), triphenyiphosphine (6.3g, 24.2 mmol), and 1-(2-hydroxyethyl)piperidine (3.9 g, 30.3 mmol) werereacted with diethyl diazodicarboxylate (DEAD) (4.2 g, 24.2 mmol) toprovide, after chromatography (silica gel, 1:1 hexane:ethyl acetate,5-20% methanol, 0.1% ammonium hydroxide) and recrystallization fromethyl acetate, 5.14 g (84%) of the title compound as a fluffy whitesolid, mp 176° C.: ¹ H NMR (300 MHz, CDCl₃) δ 8.25 (d, J=9.1 Hz, 1H),8.21 (d, J=8.8 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H),7.40 (dd, J=9.0, 2.8 Hz, 1H), 7.31 (d, J=9.7 Hz, 1H), 7.26 (cd, J=8.8Hz, 2H), 7.10 (d, J=2.7 Hz, 1H), 6.99 (d, J=8.9 Hz, 2H), 6.70 (dd,J=9.6, 2.7 Hz, 1H), 4.16 (t, J=6.0 Hz, 2H), 3.95 (s, 3H), 3.88 (s, 3H),2.81 (t, J=6.0 hz, 2H), 2.53 (m, 4H), 1.5-1.7 (m, 4H), 1.4-1.5 (m, 2H);¹³ C NMR (75 MHz, CDCl₃) δ 163.2, 159.2, 157.9, 156.9, 136.3, 135.7,133.7, 129.7, 128.3, 127.3, 126.4, 123.9, 123.7, 122.8, 120.5, 119.4,116.6, 115.7, 115.1, 109.1, 106.9, 66.2, 57.8, 55.5, 55.1, 55.0, 25.9,24.1; IR (CHCl₃) 1647, 1619 cm⁻¹ ; MS (FD) m/e 508 (M+); Anal. calc'd.for C₃₂ H₃₂ N₂ O₄ : C, 75.56; H, 6.35; N, 5.51. Found: C, 75.58; H,6.28; N, 5.77. EXAMPLE 12d ##STR96## By the procedure described forExample 14, the product of Example 12a (500 mg, 0.98 mmol) was reactedwith ethanethiol (304 mg, 4.9 mmol) and aluminum chloride (987 mg, 7.4mmol) to provide after chromatography (silica gel, 1:1 hexane:ethylacetate, 10-30% methanol, 0.1% ammonium hydroxide) and crystallizationfrom methanol 397 mg (84%) of the title compound as a white powder. Ananalytical sample was recrystallized from methanol/CHCl₃, mp 227-232d°C.: ¹ H NMR (300 MHz, DMSO-d₆) δ 10.15 (bs, 1H), 9.82 (bs, 1H), 8.43 (d,J=8.9 Hz, 1H), 8.34 (d, J=9.2 Hz, 1H), 7.69 (s, 1H), 7.63 (d, J=9.0 Hz,1H), 7.34 (d, J=8.9 Hz, 1H), 7.0-7.3 (m, 6H), 6.58 (d, J=9.6 Hz, 1H),4.13 (t, J=5.6 Hz, 2H), 2.69 (t, J=5.5 Hz, 2H), 2.46 (m, 4H), 1.3-1.6(m, 6H); ¹³ C NMR (75 MHz, DMF-d₇ /acetone-d₆ /CDCl₃) δ 162.2, 158.4,157.3, 155.9, 137.4, 137.2, 133.9, 130.8, 127.6, 127.5, 126.9, 125.0,124.0, 123.1, 121.1, 119.0, 117.3, 115.7, 115.5, 112.8, 110.6, 63.4,55.8, 53.6, 23.2, 22.1; IR (KBr) 3303, 1643, 1602 cm⁻¹ ; MS (FD) m/e 480(M+); Anal. calc'd. for C₃₀ H₂₈ N₂ O₄.0.5H₂ O: C, 73.59; H, 5.98; N,5.72. Found: C, 73.72; H, 5.88; N, 5.71. EXAMPLE 13 ##STR97## A solutionof the product of Example 12a (3.82 g, 7.51 mmol) in THF (250 mL) wastreated with lithium aluminum hydride (1.43 g, 37.5 mmol) resulting in amoderate exotherm. After the exotherm ceased, the mixture was warmed toreflux overnight, cooled to room temperature, and quenched cautiouslywith ethyl acetate (200 mL) followed by 1 N sodium hydroxide (200 mL).The layers were separated and the aqueous layer extracted with ethylacetate (2×200 mL) and the combined organic layers were washed withbrine (200 mL), dried (sodium sulfate), and concentrated. The residuewas recrystallized from hexane:ethyl acetate to provide 3.24 g (87%) ofthe title compound as an off-white solid, mp 136-137: ¹ H NMR (300 MHz,CDCl₃) δ 7.91 (d, J=8.6 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.6Hz, 1H), 7.12 (d, J=2.5 Hz, 1H), 6.95 (dd, J=9.2, 2.6, 1H), 6.91 (dd,J=8.5, 2.6 Hz, 1H), 6.6-6.8 (m, 5H), 4.75 (s, 2H), 3.95 (t, J=6.1 Hz,2H), 3.90 (s, 1H), 3.79 (s, 3H), 2.68 (t, J=6.1 Hz, 2H), 2.44 (m, 4H),1.5-1.7 (m, 4H), 1.4-1.5 (m, 2H); ¹³ C NMR (75 MHz, CDCl₃) 3 159.1,157.3, 153.4, 143.5, 137.9, 135.0, 134.1, 126.5, 125.6, 124.9, 124.2,123.8, 123.7, 122.4, 121.7, 118.1, 114.9, 113.8, 111.2, 106.4, 65.8,57.8, 55.8, 55.2, 54.8, 25.7, 24.0; IR (CHCl₃) 1506 cm⁻¹ ; MS (FD) m/e494 (M+); Anal. calc'd. for C₃₂ H₃₄ N₂ O₃ : C, 77.70; H, 6.94; N, 5.66.Found: C, 77.54; H, 6.99; N, 5.63. Test Procedure General PreparationProcedure

In the examples illustrating the methods, a post-menopausal model wasused in which effects of different treatments upon circulating lipidswere determined.

Seventy-five day old female Sprague Dawley rats (weight range of 200 to225 g) were obtained from Charles River Laboratories (Portage, Mich.).The animals were either bilaterally ovarieccomized (OVX) or exposed to aSham surgical procedure at Charles River Laboratories, and then shippedafter one week. Upon arrival, they were housed in metal hanging cages ingroups of 3 or 4 per cage and had ad libitum access to food (calciumcontent approximately 0.5%) and water for one week. Room temperature wasmaintained at 22.2°±1.70° C. with a minimum relative humidity of 40%.The photoperiod in the room was 12 hours light and 12 hours dark.

Dosing Regimen Tissue Collection. After a one week acclimation period(therefore, two weeks post--OVX) daily dosing with test compound wasinitiated. 17a-ethynyl estradiol or the test compound were given orally,unless otherwise stated, as a suspension in 1% carboxymethylcellulose crdissolved in 20% cyclodextrin. Animals were dosed daily for 4 days.Following the dosing regimen, animals were weighed and anesthetized witha ketamine: Xylazine (2:1, V:V) mixture and a blood sample was collectedby cardiac puncture. The animals were then sacrificed by asphyxiationwith CO₂, the uterus was removed through a midline incision, and a wetuterine weight was determined.

Cholesterol Analysis. Blood samples were allowed to clot at roomtemperature for 3 hours, and serum was obtained following centrifugationfor 10 minutes at 3000 rpm. Serum cholesterol was determined using aBoehringer Mannheim Diagnostics high performance cholesterol assay.Briefly the cholesterol was oxidized to cholest-4-en-3-one and hydrogenperoxide. The hydrogen peroxide was then reacted with phenol and4-aminophenazone in the presence of peroxidase to produce a p-quinoneimine dye, which was read spectrophotemetrically at 500 nm. Cholesterolconcentration was then calculated against a standard curve. The entireassay was automated using a Biomek Automated Workstation.

Uterine Eosinophil Peroxidase (EPO) Assay. Uteri were kept at 4° C.until time of enzymatic analysis. The uteri were then homogenized in 50volumes of 50 mM Tris buffer (pH -3.0) containing 0.005% Triton X-100.Upon addition of 0.01% hydrogen peroxide and 10 mM O-phenylenediamine(final concentrations) in Tris buffer, increase in absorbance wasmonitored for one minute at 450 nm. The presence of eosonophils in theuterus is an indication of estrogenic activity of a compound. Themaximal velocity of a 15 second interval was determined over theinitial, linear portion of the reaction curve.

Source of Compound: 17α-ethynyl estradiol was obtained from SigmaChemical Co., St. Louis, Mo.

Influence of Formula I and II Compounds on Serum Cholesterol andDetermination of Agonist/Non-Agonist Activity

Data presented in Table 1 below show comparative results amongovariectomized rats, rats treated with 17α-ethynyl estradiol (EE₂ ; anorally available form of estrogen) and rats treated with certaincompounds of the present invention. Although EE₂ caused a decrease inserum cholesterol when orally administered at 0.1 mg/kg/day, it alsoexerted a stimulatory action on the uterus so that EE₂ uterine weightwas substantially greater than the uterine weight of ovariectomized testanimals. This uterine response to estrogen is well recognized in theart.

Not only did the compounds of the present invention generally reduceserum cholesterol compared to the ovariectomized control animals, bututerine weight was only minimally increased to slightly decreased withthe majority of the formula compounds tested. Compared to estrogeniccompounds known in the art, the benefit of serum cholesterol reductionwithout adversely affecting uterine weight is quite rare and desirable.

As is expressed in the below data, estrogenicity also was assessed byevaluating the adverse response of eosinophil infiltration into theuterus. The compounds of the present invention did not cause anyincrease in the number of eosinophils observed in the stromal layer ofovariectomized rats, while estradiol cause a substantial, expectedincrease in eosinophil infiltration.

The data presented in the Tables 1 below reflects the response of 5 to 6rats per treatment.

                  TABLE 1                                                         ______________________________________                                                                            Serum                                         Uterine Weight  Cholesterol                                                  Dose (% increase vs. Uterine EPO (% decrease vs.                             Compound mg/kg OVX) (V. max) OVX)                                           ______________________________________                                        EE.sub.2                                                                              0.1     86.3        116.4   81.4                                        Example 1 0.1 25.3 7.8 72.8                                                    1.0 9.2 3.0 51.0                                                              10.0 5.9 2.1 54.6                                                            Example 3 0.1 32.5 4.2 51.5                                                    1.0 7.4 3.0 50.8                                                             Example 4 0.1 10 3.3 62.6                                                      1.0 15.3 3.3 48.2                                                            Example 5 0.1 -5.1 4.5 -9                                                      1.0 18.6 4.8 61.3                                                            Example 6 0.1 23 4.2 -2.5                                                      1.0 6.4 1.8 9.9                                                               10.0 50.0 3.6 -11.4                                                          Example 7 0.1 28.9 4.8 39.8                                                    1.0 31.2 6.6 65.5                                                             10.0 14.7 3.6 54.0                                                           Example 8 0.01 10.2 2.1 50.5                                                   0.1 27.4 4.8 38.5                                                             1.0 27.2 4.8 68.0                                                            Example 9 0.1 77.8 52.2 40.1                                                    109.1 83.1 54.7                                                               94.6 75.0 65.2                                                              Example 11 0.1 -8.8 2.7 17.4                                                   1.0 3 4.2 30.9                                                                10.0 -12.6 4.2 36.3                                                          Example 14 0.01 -0.6 2.7 24.8                                                  0.1 60.0 5.4 59.5                                                             1.0 49.1 36.0 60.7                                                           Example 0.1 13.6 9.3 66.4                                                     11b 1.0 7.6 12.0 73.9                                                          10.0 -4.1 7.8 61.4                                                         ______________________________________                                    

In addition to the demonstrated benefits of the compounds of the presentinvention, especially when compared to estradiol, the above data clearlydemonstrate that compounds of Formula I and II are not estrogenmimetics. Furthermore, no deleterious toxicological effects (survival)were observed with any treatment.

Osteoporosis Test Procedure Following the General Preparation Procedure,infra, the rats were treated daily for 35 days (6 rats per treatmentgroup) and sacrificed by carbon dioxide asphyxiation on the 36th day.The 35 day time period was sufficient to allow maximal reduction in bonedensity, measured as described herein. At the time of sacrifice, theuteri were removed, dissected free of extraneous tissue, and the fluidcontents were expelled before determination of wet weight in order toconfirm estrogen deficiency associated with complete ovariectomy.Uterine weight was routinely reduced about 75% in response toovariectomy. The uteri were then placed in 10% neutral buffered formalinto allow for subsequent histological analysis.

The right femurs were excised and digitilized x-rays generated andanalyzed by an image analysis program (NIH image) at the distalmetaphysis. The proximal aspect of the tibiae from these animals werealso scanned by quantitative computed tomography.

In accordance with the above procedures, compcunt's of the presentinvention and ethynyl estradiol (EE₂) in 20% hydroxypropylb-cyclodextrin were orally administered to test animals. Distal femurmetaphysis data presented in Tables 2 and 3 below are the results offormula I compound treatments compared to intact and ovariectomized testanimals. Results are reported as percent protection relative toovariectomy.

                  TABLE 2                                                         ______________________________________                                                                Distal Femur Metaphysis                                   (X-ray Image Analysis-                                                      Compound/Treatment Dose/kg Gray Score                                       ______________________________________                                        EE2            0.1 mg   62.4*                                                   Example 1 0.01 mg  14.2                                                        0.1 mg 49.8*                                                                  1.0 mg 51.7*                                                                  10.0 mg  48.2*                                                               Example 11b 0.01 mg  45.6*                                                     0.1 mg 38.5*                                                                  1.0 mg 58.5*                                                                  10.0 mg  37.3*                                                             ______________________________________                                         *P <= 0.5 two tailed Student's T Test on raw data.                       

In summary, ovariectomy of the test animals caused a significantreduction in femur density compared to intact, vehicle treated controls.Orally administered ethynyl estradiol (EE₂) prevented this loss, but therisk of uterine stimulation with this treatment is ever-present.

The compounds of the present invention also prevented bone loss in ageneral, dose-dependent manner. Accordingly, the compounds of thepresent invention are useful for the treatment of post-menopausalsyndrome, particularly osteoporosis.

MCF-7 Proliferation Assay

MCF-7 breast adenocarcinoma cells (ATCC HTB 22) were maintained in MEM(minimal essential medium, phenol red-free, Sigma, St. Louis, Mo.)supplimented with 10% fetal bovine serum (FBS) (V/V), L-glutamine (2mm), sodium pyruvate (1 mM), HEPES{(N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]10 mM},non-essential amino acids and bovine insulin (1 ug/mL) (maintenancemedium). Ten days prior to assay, MCF-7 cells were switched tomaintenance medium supplemented with 10% dextran coated charcoalstripped fetal bovine serum (DCC-FBS) assay medium) in place of 10% FBSto deplete internal stores of steroids. MCF-7 cells were removed frommaintenance flasks using cell dissociation medium (Ca++/Mg++ free HBSS(phenol red-free) supplemented with 10 mM HEPES and 2 mM EDTA). Cellswere washed twice with assay medium and adjusted to 80,000 cells/mL.Approximately 100 mL (8,000 cells) were added to flat-bottommicroculture wells (Costar 3596) and incubated at 37° C. in a 5% CO₂humidified incubator for 48 hours to allow for cell adherence andequilibration after transfer. Serial dilutions of drugs or DMSO as adiluent control were prepared in assay medium and 50 mL transferred totriplicate microcultures followed by 50 mL assay medium for a finalvolume of 200 mL. After an additional 48 hours at 37° C. in a 5% CO₂humidified incubator, microcultures were pulsed with tritiated thymidine(1 uCi/well) for 4 hours. Cultures were terminated by freezing at -70°C. for 24 hours followed by thawing and harvesting of microculturesusing a Skatron Semiautomatic Cell Harvester. Samples were counted byliquid scintillation using a Wallac BetaPlace b counter. Results inTable 3 below show the IC₅₀ for certain compounds of the presentinvention.

                  TABLE 3                                                         ______________________________________                                        Compound (Example Reference)                                                                      IC.sub.50 nM                                              ______________________________________                                        1                   0.2                                                         2 100                                                                         3 3.0                                                                         4 5.0                                                                         5 1000                                                                        6 500                                                                         11 0.7                                                                        14 1                                                                        ______________________________________                                    

DMBA-Induced Mammary Tumor Inhibition

Estrogen-dependent mammary tumors are produced in female Sprague-Dawleyeats which are purchased from Harlan Industries, Indianapolis, Ind. Atabout 55 days of age, the rats receive a single oral feeding of 20 mg of7,12-dimethylbenz[a]anthracene (DMBA). About 6 weeks after DMBAadministration, the mammary glands are palpated at weekly intervals forthe appearance of tumors. Whenever one or more tumors appear, thelongest and shortest diameters of each tumor are measured with a metriccaliper, the measurements are recorded, and that animal is selected forexperimentation. An attempt is made to uniformly distribute the varioussizes of tumors in the treated and control groups such thataverage-sized tumors are equivalently distributed between test groups.Control groups and test groups for each experiment contain 5 to 9animals.

Compounds of Formula I are administered either through intraperitonealinjections in 2% acacia, or orally. orally administered compounds areeither dissolved or suspended in 0.2 mL corn oil. Each treatment,including acacia and corn oil control treatments, is administered oncedaily to each test animal. Following the initial tumor measurement andselection of test animals, tumors are measured each week by theabove-mentioned method. The treatment and measurements of animalscontinue for 3 to 5 weeks at which time the final areas of the tumorsare determined. For each compound and control treatment, the change inthe mean tumor area is determined.

Uterine Fibrosis Test Procedures

Test 1

Between and 20 women having uterine fibrosis are administered a compoundof the present invention. The amount of compound administered is from0.1 to 1000 mg/day, and the period of administration is 3 months.

The women are observed during the period of administration, and up LO 3months after discontinuance of administration, for effects on uterinefibrosis.

Test 2

The same procedure is used as in Test 1, except the period ofadministration is 6 months.

Test 3

The same procedure is used as in Test 1, except the period ofadministration is 1 year.

Test 4

A. Induction of fibroid tumors in guinea pig.

Prolonged estrogen stimulation is used to induce leiomyomata in sexuallymature female guinea pigs. Animals are dosed with estradiol 3-5 timesper week by injection for 2-4 months or until tumors arise. Treatmentsconsisting of a compound of the invention or vehicle is administereddaily for 3-16 weeks and then animals are sacrificed and the uteriharvested and analyzed for tumor regression.

B. Implantation of human uterine fibroid tissue in nude mice.

Tissue from human leiomyomas are implanted into the peritoneal cavityand or uterine myometrium of sexually mature, castrated, female, nudemice. Exogenous estrogen are supplied to induce growth of the explantedtissue. In some cases, the harvested tumor cells are cultured in vitroprior to implantation. Treatment consisting of a compound of the presentinvention or vehicle is supplied by gastric gavage on a daily basis for3-16 weeks and implants are removed and measured for growth orregression. At the time of sacrifice, the uteri are harvested to assessthe status of the organ.

Test 5

A. Tissue from human uterine fibroid tumors is harvested and maintained,in vitro, as primary nontransformed cultures. Surgical specimens arepushed through a sterile mesh or sieve, or alternately teased apart fromsurrounding tissue to produce a single cell suspension. Cells aremaintained in media containing 10% serum and antibiotic. Rates of growthin the presence and absence of estrogen are determined. Cells areassayed for heir ability to produce complement component C3 and theirresponse to growth factors and growth hormone. In vitro cultures areassessed for their proliferative response following treatment withprogestins, GnRH, a compound of the present invention and vehicle.Levels of steroid hormone receptors are assessed weekly to determinewhether important cell characteristics are maintained in vitro. Tissuefrom 5-25 patients are utilized.

Activity in at least one of the above tests indicates the compounds ofthe present invention are of potential in the treatment of uterinefibrosis.

Endometriosis Test Procedure

In Tests 1 and 2, effects of 14-day and 21-day administration ofcompounds of the present invention on the growth of explantedendometrial tissue can be examined.

Test 1

Twelve to thirty adult CD strain female rats are used as test animals.They are divided into three groups of equal numbers. The estrous cycleof all animals is monitored. On the day of proestrus, surgery isperformed on each female. Females in each group have the left uterinehorn removed, sectioned into small squares, and the squares are looselysutured at various sites adjacent to the mesenteric blood flow. Inaddition, females in Group 2 have the ovaries removed.

On the day following surgery, animals in Groups 1 and 2 receiveintraperitoneal injections of water for 14 days whereas animals in Group3 receive intraperitoneal injections of 1.0 mg of a compound of thepresent invention per kilogram of body weight for the same duration.Following 14 days of treatment, each female is sacrificed and theendometrial explants, adrenals, remaining uterus, and ovaries, whereapplicable, are removed and prepared for histological examination. Theovaries and adrenals are weighed.

Test 2

Twelve to thirty adult CD strain female rats are used as test animals.They are divided into two equal groups. The estrous cycle of all animalsis monitored. On the day of proestrus, surgery is performed on eachfemale. Females in each group have the left uterine horn removed,sectioned into small squares, and the squares are loosely sutured atvarious sites adjacent to the mesenteric blood flow.

Approximately 50 days following surgery, animals assigned to Group 1receive intraperitoneal injections of water for 21 days whereas animalsin Group 2 receive intraperitoneal injections of 1.0 mg of a compound ofthe present invention per kilogram of body weight for the same duration.Following 21 days of treatment, each female is sacrificed and theendometrial explants and adrenals are removed and weighed. The explantsare measured as an indication of growth. Estrous cycles are monitored.

Test 3

A. Surgical induction of endometriosis

Autographs of endometrial tissue are used to induce endometriosis inrats and/or rabbits. Female animals at reproductive maturity undergobilateral oophorectomy, and estrogen is supplied exogenously thusproviding a specific and constant level of hormone. Autologousendometrial tissue is implanted in the peritoneum of 5-150 animals andestrogen supplied to induce growth of the explanted tissue. Treatmentconsisting of a compound of the present invention is supplied by gastriclavage on a daily basis for 3-16 weeks, and implants are removed andmeasured for growth or regression. At the time of sacrifice, the intacthorn of the uterus is harvested to assess status of endometrium.

B. Implantation of human endometrial tissue in nude mice.

Tissue from human endometrial lesions is implanted into the peritoneumof sexually mature, castrated, female, nude mice. Exogenous estrogen issupplied to induce growth of the explanted tissue. In some cases, theharvested endometrial cells are cultured in vitro prior to implantation.Treatment consisting of a compound of the present invention supplied bygastric gavage on a daily basis for 3-16 weeks, and implants are removedand measured for growth or regression. At the time of sacrifice, theuteri are harvested to assess the status of the intact endometrium.

Test 4

A. Tissue from human endometrial lesions is harvested and maintained invitro as primary nontransformed cultures. Surgical specimens are pushedthrough a sterile mesh or sieve, or alternately teased apart fromsurrounding tissue to produce a single cell suspension. Cells aremaintained in media containing 10% serum and antibiotic. Rates of growthin the presence and absence of estrogen are determined. Cells areassayed for their ability to produce complement component C3 and theirresponse to growth factors and growth hormone. In vitro cultures areassessed for their proliferative response following treatment withprogestins, GnRH, a compound of the invention, and vehicle. Levels ofsteroid hormone receptors are assessed weekly to determine whetherimportant cell characteristics are maintained in vitro. Tissue from 5-25patients is utilized.

Activity in any of the above assays indicates that the compounds of thepresent invention are useful in the treatment of endometriosis.

Inhibition of Aortal Smooth Cell Proliferation/Restenosis Test Procedure

Compounds of the present invention have capacity to inhibit aortalsmooth cell proliferation. This can be demonstrated by using culturedsmooth cells derived from rabbit aorta, proliferation being determinedby the measurement of DNA synthesis. Cells are obtained by explantmethod as described in Ross, J. of Cell Bio. 50: 172 (1971). Cells areplated in 96 well microtiter plates for five days. The cultures becomeconfluent and growth arrested. The cells are then transferred toDulbecco's Modified Eagle's Medium (DMEM) containing 0.5-2% plateletpoor plasma, 2 mM L-glutamine, 100 U/mi penicillin, 100 mg mlstreptomycin, 1 mC/ml ³ H-thymidine, 20 ng/ml platelet-derived growthfactor, and varying concentrations of the present compounds. Stocksolution of the compounds is prepared in dimethyl sulphoxide and thendiluted to appropriate concentration (0.01-30 mM) in the above assaymedium. Cells are then incubated at 37° C. for 24 hours under 5% CO₂/95% air. At the end of 24 hours, the cells are fixed in methanol. 3Hthymidine incorporation in DNA is then determined by scintillationcounting as described in Bonin, et al., Exp. Cell Res. 181: 475-482(1989).

Inhibition of aortal smooth muscle cell proliferation by the compoundsof the present invention are further demonstrated by determining theireffects on exponentially growing cells. Smooth muscle cells from rabbitaortae are seeded in 12 well tissue culture plates in DMEM containing10% fetal bovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100mg/ml streptomycin. After 24 hours, the cells are attached and themedium is replaced with DMEM containing 10% serum, 2 mM L-glutamine, 100U/ml penicillin, 100 mg/ml streptomycin, and desired concentrations ofthe compounds. Cells are allowed to grow for four days. Cells aretreated with trypsin and the number of cells in each culture isdetermined by counting using a ZM-Coulter counter.

Activity in the above tests indicates that the compounds of the presentinvention are of potential in the treatment of restenosis.

The present invention also provides a method of alleviatingpost-menopausal syndrome in women which comprises the aforementionedmethod using compounds of Formula I and further comprises administeringto a woman an effective amount of estrogen or progestin. Thesetreatments are particularly useful for treating osteoporosis andlowering serum cholesterol because the patient will receive the benefitsof each pharmaceutical agent while the compounds of the presentinvention would inhibit undesirable side-effects of estrogen andprogestin. Activity of these combination treatments in any of thepost-menopausal tests, infra, indicates that the combination treatmentsare useful for alleviating the symptoms of post-menopausal symptoms inwomen.

Various forms of estrogen and progestin are commercially available.Estrogen-based agents include, for example, ethynyl estrogen (0.01-0.03mg/day), mestranol (0.05-0.15 mg/day), and conjugated estrogenichormones such as Premarin® (Wyeth-Ayerst; 0.3-2.5 mg/day).Progestin-based agents include, for example, medroxyprogesterone such asProvera® (Upjohn; 2.5-10 mg/day), norethylnodrel (1.0-10.0 mg/day), andnonethindrone (0.5-2.0 mg/day). A preferred estrogen-based compound isPremarin, and norethylnodrel and norethindrone are preferredprogestin-based agents.

The method of administration of each estrogen- and progestin-based agentis consistent with that which is known in the art. For the majority ofthe methods of the present invention, compounds of Formula I and II areadministered continuously, from 1 to 3 times daily. However, cyclicaltherapy may especially be useful in the treatment of endometriosis ormay be used acutely during painful attacks of the disease. In the caseof restenosis, therapy may be limited to short (1-6 months) intervalsfollowing medical procedures such as angioplasty.

As used herein, the term "effective amount" means an amount of compoundof the present invention which is capable of alleviating the symptoms ofthe various pathological conditions herein described. The specific doseof a compound administered according to this invention will, of course,be determined by the particular circumstances surrounding the caseincluding, for example, the compound administered, the route ofadministration, the state of being of the patient, and the pathologicalcondition being treated. A typical daily dose will contain a nontoxicdosage level of from about 5 mg to about 600 mg/day of a compound of thepresent invention. Preferred daily doses generally will be from about 15mg to about 80 mg/day.

The compounds of this invention can be administered by a variety ofroutes including oral, rectal, transdermal, subucutaneus, intravenous,intramuscular, and intranasal. These compounds preferably are formulatedprior to administration, the selection of which will be decided by theattending physician. Thus, another aspect of the present invention is apharmaceutical composition comprising an effective amount of a compoundof Formula I or II, or a pharmaceutically acceptable salt thereof,optionally containing an effective amount of estrogen or progestin, anda pharmaceutically acceptable carrier, diluent, or excipient.

The total active ingredients in such formulations comprises from 0.1% to99.9% by weight of the formulation. By "pharmaceutically acceptable" itis meant the carrier, diluent, excipients and salt must be compatiblewith the other ingredients of the formulation, and not deleterious tothe recipient thereof.

Pharmaceutical formulations of the present invention can be prepared byprocedures known in the art using well known and readily availableingredients. For example, the compounds of formula I and II, with orwithout an estrogen or progestin compound, can be formulated with commonexcipients, diluents, or carriers, and formed into tablets, capsules,suspensions, powders, and the like. Examples of excipients, diluents,and carriers that are suitable for such formulations include thefollowing: fillers and extenders such as starch, sugars, mannitol, andsilicic derivatives; binding agents such as carboxymethyl cellulose andother cellulose derivatives, alginates, gelatin, andpolyvinyl-pyrrolidone; moisturizing agents such as glycerol;disintegrating agents such as calcium carbonate and sodium bicarbonate;agents for retarding dissolution such as paraffin; resorptionaccelerators such as quaternary ammonium compounds; surface activeagents such as cetyl alcohol, glycerol monostearate; adsorptive carrierssuch as kaolin and bentonite; and lubricants such as talc, calcium andmagnesium stearate, and solid polyethyl glycols.

The compounds also can be formulated as elixirs or solutions forconvenient oral administration or as solutions appropriate forparenteral administration, for example, by intramuscular, subcutaneousor intravenous routes. Additionally, the compounds are well suited toformulation as sustained release dosage forms and the like. Theformulations can be so constituted that they release the activeingredient only or preferably in a particular physiological location,possibly over a period of time. The coatings, envelopes, and protectivematrices may be made, for example, from polymeric substances or waxes.

Compounds of formula I and II, alone or in combination with apharmaceutical agent of the present invention, generally will beadministered in a convenient formulation. The following formulationexamples only are illustrative and are not intended to limit the scopeof the present invention.

Formulations

In the formulations which follow, "active ingredient" means a compoundof formula I or II, or a salt or solvate thereof.

    ______________________________________                                        Formulation 1: Gelatin Capsules                                                 Hard gelatin capsules are prepared using the following:                          Ingredient       Quantity (mg/capsule)                                   ______________________________________                                        Active ingredient 0.1-1000                                                      Starch, NF 0-650                                                              Starch flowable powder 0-650                                                  Silicone fluid 350 centistokes 0-15                                         ______________________________________                                    

The formulation above may be changed in compliance with the reasonablevariations provided.

A tablet formulation is prepared using the ingredients below:

    ______________________________________                                        Formulation 2: Tablets                                                              Ingredient      Quantity (mg/tablet)                                    ______________________________________                                        Active ingredient  2.5-1000                                                     Cellulose, microcrystalline 200-650                                           Silicon dioxide, fumed 10-650                                                 Stearate acid 5-15                                                          ______________________________________                                    

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 2.5-1000 mg of active ingredientare made up as follows:

    ______________________________________                                        Formulation 3: Tablets                                                             Ingredient        Quantity (mg/tablet)                                   ______________________________________                                        Active ingredient  25-1000                                                      Starch 45                                                                     Cellulose, microcrystalline 35                                                Polyvinylpyrrolidone 4                                                        (as 10% solution in water)                                                    Sodium carboxymethyl cellulose 4.5                                            Magnesium stearate 0.5                                                        Talc 1                                                                      ______________________________________                                    

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Suspensions each containing 0.1-1000 mg of medicament per 5 ml dose aremade as follows:

    ______________________________________                                        Formulation 4: Suspensions                                                         Ingredient          Quantity (mg/5 ml)                                   ______________________________________                                        Active ingredient    0.1-1000  mg                                               Sodium carboxymethyl cellulose 50 mg                                          Syrup 1.25 mg                                                                 Benzoic acid solution 0.10 mL                                                 Flavor q.v.                                                                   Color q.v.                                                                    Purified water to 5 mL                                                      ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor, and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

An aerosol solution is prepared containing the following ingredients:

    ______________________________________                                        Formulation 5: Aerosol                                                            Ingredient           Quantity (% by weight)                               ______________________________________                                        Active ingredient     0.25                                                      Ethanol 25.75                                                                 Propellant 22 (Chlorodifluoromethane) 70.00                                 ______________________________________                                    

The active ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C., and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remaining propellant. The valve units arethen fitted to the container.

Suppositories are prepared as follows:

    ______________________________________                                        Formulation 6: Suppositories                                                      Ingredient       Quantity (mg/suppository)                                ______________________________________                                        Active ingredient                                                                              250                                                            Saturated fatty acid glycerides 2,000                                       ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimal necessary heat. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

An intravenous formulation is prepared as follows:

    ______________________________________                                        Formulation 7: Intravenous Solution                                                   Ingredient  Quantity                                                  ______________________________________                                        Active ingredient                                                                               50 mg                                                         Isotonic saline 1,000 mL                                                    ______________________________________                                    

The solution of the above ingredients is intravenously administered to apatient at a rate of about 1 mL per minute.

    ______________________________________                                        Formulation 8: Combination Capsule I                                                Ingredient  Quantity (mg/capsule)                                       ______________________________________                                        Active ingredient                                                                           50                                                                Premarin 1                                                                    Avicel pH 101 50                                                              Starch 1500 117.50                                                            Silicon Oil 2                                                                 Tween 80 0.50                                                                 Cab-O-Sil 0.25                                                              ______________________________________                                    

    ______________________________________                                        Formulation 9: Combination Capsule II                                               Ingredient  Quantity (mg/capsule)                                       ______________________________________                                        Active ingredient                                                                           50                                                                Norethylnodrel 5                                                              Avicel pH 101 82.50                                                           Starch 1500 90                                                                Silicon Oil 2                                                                 Tween 80 0.50                                                               ______________________________________                                    

    ______________________________________                                        Formulation 10: Combination Tablet                                                  Ingredient   Quantity (mg/capsule)                                      ______________________________________                                        Active ingredient                                                                            50                                                               Premarin 1                                                                    Corn Starch NF 50                                                             Povidone, K29-32 6                                                            Avicel pH 101 41.50                                                           Avicel pH 102 136.50                                                          Crospovidone XL10 2.50                                                        Magnesium Stearate 0.50                                                       Cab-O-Sil 0.50                                                              ______________________________________                                    

The compounds of the present invention may contain one or moreassymetric centers, and therefore can exist as a mixture of isomers, oras individual isomers. Either a mixture or individual isomers will beuseful for the purposes of the present invention, and can be soemployed.

I claim:
 1. An individual isomer selected from the group consisting of:##STR98## or a pharmaceutically acceptable salt thereof.
 2. The isomeraccording to claim 1 which is the hydrochloride salt.
 3. Apharmaceutical composition comprising an isomer according to claim 2together with a pharmaceutically acceptable carrier, diluent orexcipient.
 4. A method for inhibiting bone loss or bone resorptioncomprising administering to a patient in need thereof an effectiveamount of an isomer of claim
 2. 5. A method according to claim 4 whereinsaid bone loss or bone resorption is due to menopause or ovariectomy. 6.A method of lowering serum cholesterol levels comprising administeringto a patient in need thereof an effective amount of an isomer of claim2.
 7. A method of inhibiting estrogen-dependent cancer comprisingadministering to a patient in need thereof an effective amount of anisomer of claim
 2. 8. The method according to claim 7 wherein the canceris breast cancer.